ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.424G>A (p.Val142Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000371.4(TTR):c.424G>A (p.Val142Ile)
Variation ID: 13426 Accession: VCV000013426.89
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q12.1 18: 31598655 (GRCh38) [ NCBI UCSC ] 18: 29178618 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Aug 11, 2024 Jun 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000371.4:c.424G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Val142Ile missense NC_000018.10:g.31598655G>A NC_000018.9:g.29178618G>A NG_009490.1:g.11889G>A LRG_416:g.11889G>A LRG_416t1:c.424G>A LRG_416p1:p.Val142Ile P02766:p.Val142Ile - Protein change
- V142I
- Other names
- V122I
- p.V142I:GTC>ATC
- Canonical SPDI
- NC_000018.10:31598654:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00559 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00113
Exome Aggregation Consortium (ExAC) 0.00138
The Genome Aggregation Database (gnomAD) 0.00501
1000 Genomes Project 0.00559
Trans-Omics for Precision Medicine (TOPMed) 0.00560
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00592
1000 Genomes Project 30x 0.00609
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTR | - | - |
GRCh38 GRCh37 |
373 | 420 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (18) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000014368.71 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 18, 2011 | RCV000030575.10 | |
Pathogenic (16) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV000078674.63 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 30, 2023 | RCV000211747.14 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 13, 2024 | RCV000243161.14 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000735409.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001173290.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 12, 2019 | RCV000853387.9 | |
TTR-related disorder
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV003335038.2 |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2022 | RCV002476965.8 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 19, 2022 | RCV003319166.8 | |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 10, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331406.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 6
Sex: mixed
|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140876.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336374.1
First in ClinVar: Feb 07, 2021 Last updated: Feb 07, 2021 |
|
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Pathogenic
(Mar 30, 2020)
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criteria provided, single submitter
Method: clinical testing
|
ATTRV30M amyloidosis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060031.6
First in ClinVar: May 03, 2013 Last updated: Apr 15, 2020 |
Comment:
The p.Val142Ile variant in TTR (alternate nomenclature p.Val122Ile) has been reported in >70 predominantly African American individuals with confirmed cardiac amyloidosis that presented with clinical … (more)
The p.Val142Ile variant in TTR (alternate nomenclature p.Val122Ile) has been reported in >70 predominantly African American individuals with confirmed cardiac amyloidosis that presented with clinical features of cardiomyopathy or heart failure that typically presented with a later onset (after age 60-70). It is believed to be the most common variant identified, particularly amongst elderly African Americans (Jacobson 1997, Conners 2009, Lee 2011, Ruberg 2012, Arruda-Olsen 2013, Damy 2016). Individuals homozygous for the variant have been reported to have earlier onset of symptoms (Reddi 2014, Liu 2014). This variant has been shown to increase the risk for congestive heart failure in older individuals (>70 years), with two small studies reporting an age adjusted odds ratio of 1.5-2 [95% CI 1.2-2.7] (Quarta 2015, Damrauer 2019). Additionally, this variant has also been reported as a pathogenic variant by several clinical laboratories in ClinVar (Variation ID 13426). It is present in 1.6% (405/24968) of African chromosomes by gnomAD, including 3 homozygotes. Although this frequency is high in the general population, it is consistent with the age-dependent and possibly reduced penetrance of this disease. This variant has been shown to render the TTR protein complex unstable, causing misfolding and deposits in the myocardium (Jiang 2001, Askansas 2003). In summary, this variant is pathogenic for autosomal dominant late-onset transthyretin amyloidosis, though penetrance may not be complete. (less)
Number of individuals with the variant: 27
|
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Pathogenic
(Nov 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449972.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Number of individuals with the variant: 1
|
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061278.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.424G>A;p.(Val142Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13426; OMIM: 176300.0009; PMID: 12874414; … (more)
The c.424G>A;p.(Val142Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13426; OMIM: 176300.0009; PMID: 12874414; PMID: 25551524; PMID: 30938420; PMID: 31359320; PMID: 27720586; PMID: 26123279; PMID:11752443) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12874414, 27758856, 27720586, 11752443) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (TR_THY domain) - PM1. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 6
Sex: mixed
Geographic origin: Brazil
|
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pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
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Isolated Cardiac Amyloidosis
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053250.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 10
Observation 2:
Tissue: Blood
Observation 3:
Tissue: Blood
Observation 4:
Tissue: Blood
Observation 5:
Tissue: Blood
Observation 6:
Tissue: Blood
Observation 7:
Tissue: Blood
|
|
Pathogenic
(Nov 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Variantyx, Inc.
Accession: SCV002754521.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This is a nonsynonymous variant in the TTR gene (OMIM 176300). Heterozygous pathogenic variants in this gene are associated with autosomal dominant hereditary transthyretin-related amyloidosis. … (more)
This is a nonsynonymous variant in the TTR gene (OMIM 176300). Heterozygous pathogenic variants in this gene are associated with autosomal dominant hereditary transthyretin-related amyloidosis. This is an established founder variant in the African population, with an allele frequency of >3% in African Americans (PMID: 9017939, 26123279). It has been observed in individuals with transthyretin-related amyloidosis in both the homozygous and the heterozygous state (PMID: 25846356, 24184229, 12050338, 19781421, 22745357) (PS4). Functional studies have shown that this variant alters TTR protein function (PMID: 11752443, 12874414, 15820680, 17503405, 22184092, 24474780) (PS3). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant has a 1.654% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on current evidence, this variant is classified as pathogenic for autosomal dominant hereditary transthyretin-related amyloidosis. (less)
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Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841759.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common … (more)
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11752443). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013426). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11752443, 2349941, 25551524, 25819286, 26537620). Different missense changes at the same codon (p.Val142Ala, p.Val142Leu) have been reported to be associated with TTR related disorder (ClinVar ID: VCV001333466 / PMID: 10211412, 24101130 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present) , Congestive heart failure (present)
|
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Pathogenic
(Sep 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806882.3
First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023 |
Comment:
ACMG classification criteria: PS3 strong, PS4 strong, PP1 strong
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
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Pathogenic
(Mar 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV000408397.3
First in ClinVar: Dec 06, 2016 Last updated: Jul 22, 2023 |
Comment:
The TTR c.424G>A (p.Val142Ile) missense variant results in the substitution of valine at amino acid position at 142 with isoleucine. This variant, which is also … (more)
The TTR c.424G>A (p.Val142Ile) missense variant results in the substitution of valine at amino acid position at 142 with isoleucine. This variant, which is also known as p.Val122Ile, has been described as one of the most common pathogenic variants associated with hereditary transthyretin amyloidosis and is present in a heterozygous state at a frequency of approximately 3.5% in the African American population (PMID: 20301373; PMID: 26123279). The c.424G>A variant is generally associated with cardiac amyloidosis with either limited or no significant neurological involvement (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). However, additional phenotypes have been observed which include gait abnormalities, gastrointestinal and urinary phenotypes, muscle weakness, carpal tunnel syndrome, spinal stenosis, and neurologic features including tingling, numbness, and neuropathic pain (PMID: 25819286; PMID: 27386769; PMID: 27838833; PMID: 31135624; PMID: 33467513). Phenotype severity generally increases after the age of 60 and can include congestive heart failure (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). Penetrance is incomplete and variable by ethnic origin and geographic region (PMID: 20301373). While hereditary transthyretin amyloidosis is inherited in an autosomal dominant pattern, homozygous and compound heterozygous individuals are also reported: across a selection of the available literature, the c.424G>A variant is found in a homozygous state in 19 patients, in a compound heterozygous state in two patients, and in a heterozygous state in 36 patients (PMID: 2349941; PMID: 9017939; PMID: 20435197; PMID: 24073013; PMID: 24184229; PMID: 24633258; PMID: 25819286; PMID: 25551524; PMID: 26537620; PMID: 26428663). The highest frequency of this allele in the Genome Aggregation Database is 0.01654 in the African/African American population (version 3.1.2). This allele frequency is high but is consistent with disease prevalence estimates in specific populations. Functional studies showed that the variant demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID: 11752443; PMID: 18276611). Based on the available evidence, the c.424G>A (p.Val142Ile) variant is classified as pathogenic for hereditary transthyretin amyloidosis. (less)
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Pathogenic
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605508.10
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The TTR c.424G>A; p.Val142Ile variant (rs76992529), also known as Val122Ile, is one of the most common pathogenic variants associated with late-onset amyloidosis in individuals often … (more)
The TTR c.424G>A; p.Val142Ile variant (rs76992529), also known as Val122Ile, is one of the most common pathogenic variants associated with late-onset amyloidosis in individuals often of African American ancestry (Buxbaum 2017, Damy 2016, Jacobson 2016) and is classified as pathogenic by several sources in the ClinVar database (Variation ID: 13426). The variant does not appear to have an effect on cardiac function until after the age of 60 (Buxbaum 2010, Reddi 2014, Quarta 2015). Although this variant commonly has a predominant clinical expression of hypertrophic restrictive cardiomyopathy with mild or no neurological symptoms, it has also been reported in an individual with neurological findings and no cardiac involvement (Stancanelli 2017). Functional studies have demonstrated instability of the variant tetramer protein (Altland 2007, Jiang 2001, Sekijima 2005, Steward 2008), and suggest the variant predisposes to accumulation of amyloid beta peptide as well as causes vacuolar degeneration leading to decreased viability of cultured skeletal muscle (Askanas 2003). This variant is found in the African/African American population with an allele frequency of 1.6% (405/24,968 alleles, including 3 homozygotes) in the Genome Aggregation Database. Although the allele frequency is high, it is consistent with the disease prevalence. The valine at codon 142 is highly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.645). Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. PMID: 17503405. Askanas V et al. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003 Jul 22;61(2):257-60. PMID: 12874414. Buxbaum J et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010 May;159(5):864-70. PMID: 20435197. Buxbaum JN et al. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017 Jul;19(7):733-742. PMID: 28102864. Damy T et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016 Jun 14;37(23):1826-34. PMID: 26537620. Jacobson DR et al. The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med. 2016 Jul 14;4(5):548-56. PMID: 27652282. Jiang X et al. The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14943-8. PMID: 11752443. Reddi HV et al. Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life. J Mol Diagn. 2014 Jan;16(1):68-74. PMID: 24184229. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. PMID: 15820680. Stancanelli C et al. Phenotypic variability of TTR Val122Ile mutation: a Caucasian patient with axonal neuropathy and normal heart. Neurol Sci. 2017 Mar;38(3):525-526. PMID: 27838833. Steward RE et al. Different disease-causing mutations in transthyretin trigger the same conformational conversion. Protein Eng Des Sel. 2008 Mar;21(3):187-95. PMID: 18276611. Quarta CC et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 1;372(1):21-9. PMID: 25551524. (less)
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Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
TTR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116698.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The TTR c.424G>A variant is predicted to result in the amino acid substitution p.Val142Ile. This variant, also referred to as p.Val122Ile using legacy nomenclature, has … (more)
The TTR c.424G>A variant is predicted to result in the amino acid substitution p.Val142Ile. This variant, also referred to as p.Val122Ile using legacy nomenclature, has been reported to be causative for autosomal dominant hereditary amyloidosis and typically presents as familial amyloid cardiomyopathy (Ando et al. 2013. PubMed ID: 23425518; Penchala et al. 2013. PubMed ID: 23716704; Jacobson et al. 1990. PubMed ID: 2349941; Buxbaum et al. 2010. PubMed ID: 20435197; Dungu et al. 2016. PubMed ID: 27618855; Lopes et al. 2019. PubMed ID: 31554435). It has also been reported as pathogenic by multiple, independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/). This variant is reported in 1.6% of alleles in individuals of African descent in gnomAD, which is consistent with variant being a founder event with high frequency in individuals of African descent (Jacobson et al. 1997. PubMed ID: 9017939; Jacobson et al. 2015. PubMed ID: 26123279). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
germline
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045089.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
The TTR c.424G>A (p.Val142Ile) variant, also known as Val122Ile, has been reported in many individuals of predominantly African American ancestry affected with cardiac amyloidosis and … (more)
The TTR c.424G>A (p.Val142Ile) variant, also known as Val122Ile, has been reported in many individuals of predominantly African American ancestry affected with cardiac amyloidosis and late onset cardiomyopathy or congestive heart failure and has been shown to have an age-adjusted odds ratio of 1.5-2 [95% CI 1.2-2.7] (Damrauer SM et al., PMID: 31821430; Dungu JN et al., PMID: 27618855; Jacobson DR et al., PMID: 27652282; Quarta CC et al., PMID: 25551524; Reddi HV et al., PMID: 24184229). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.6% in the African/African American population, which is consistent with a reduced penetrance and age-dependent variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to transthyretin function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715218.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 02, 2024 |
Comment:
PS3, PS4
Number of individuals with the variant: 56
|
|
Pathogenic
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563460.14
First in ClinVar: Aug 23, 2022 Last updated: Aug 04, 2024 |
Comment:
TTR: PP1:Strong, PS4, PS3:Moderate
Number of individuals with the variant: 4
|
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Pathogenic
(May 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary transthyretin amyloidosis
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995173.1
First in ClinVar: Oct 11, 2019 Last updated: Oct 11, 2019 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Mar 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Transthyretin related familial amyloid cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996263.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy. It is present in the heterozygous state in the … (more)
This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (417/277140), including three reports of hymozygous individuals. The p.Val142Ile is found in approximately 3.5% of African Americans. In silico analyses support a deleterious effect of the c.424G>A, p.Val142Ile variant on protein function. This variant is clearly defined as a late-onset cardiac amyloidosis causative allele (PMID: 24070600, 24184229). It is a common cause of amyloidosis in individuals of African American ancestry and typically causes symptoms after the sixth decade of life (PMID: 20435197, 22877808). It has also been observed in individuals from other populations and causes the same phenotype (PMID: 25846356, 22745357). ClinVar contains an entry for this variant (Variation ID: 13426). Experimental studies have shown that this missense change weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Jun 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433271.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Anemia
Bone marrow hypocellularity Pancytopenia
Affected status: yes
Allele origin:
germline
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854564.2
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: male
|
|
Pathogenic
(Dec 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209380.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
Originated in a small number of founder carriers in southern West Africa (Jacobson et al., 2016); Reported as heterozygous or homozygous in individuals with familial … (more)
Originated in a small number of founder carriers in southern West Africa (Jacobson et al., 2016); Reported as heterozygous or homozygous in individuals with familial amyloid cardiomyopathy and senile systemic amyloidosis (SSA); these disorders usually have an age-dependent penetrance with onset later in life (age > 50-60 years), characterized by amyloid deposits in the heart leading to congestive heart failure and conduction system disturbances (Jacobson et al., 1997a; Jacobson et al., 1997b); Reported in individuals of varying ethnic backgrounds in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014); Cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations (Askanas et al., 2003); Renders the TTR complex unstable, leading to unfolding and lower tetramer stability (Jiang et al., 2001); This variant is associated with the following publications: (PMID: 18276611, 24474780, 22083004, 24633258, 27618855, 25997029, 26537620, 29520877, 31371117, 31821430, 20301373, 15820680, 17503405, 11752443, 12874414, 9017939, 25551524, 22995991, 23713495, 23716704, 22745357, 20435197, 24184229, 22184092, 24818650, 22877808, 20981092, 26894299, 26428663, 24070600, 2349941, 27652282, 28090011, 26243339, 27364045, 25819286, 26002815, 26123279, 27386769, 26017327, 28335735, 27838833, 28635949, 28944235, 29052438, 29073801, 28870641, 29016222, 30093168, 28475415, 29764897, 30683924, 31659433, 31740141, 31554435, 32674397, 32150461, 31980526, 31589614, 32269295, 26656838, 32399692, 32376792) (less)
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Pathogenic
(Mar 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502738.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 59
Secondary finding: no
|
|
Pathogenic
(Apr 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Carpal tunnel syndrome 1 Hyperthyroxinemia, dystransthyretinemic
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611333.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Aug 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown, yes
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001441407.2 First in ClinVar: Feb 07, 2021 Last updated: May 20, 2023 |
Comment:
The c.424G>A variant in TTR is an established pathogenic variant in individuals of African American ancestry with hereditary transthyretin (ATTR) amyloidosis related cardiomyopathy as it … (more)
The c.424G>A variant in TTR is an established pathogenic variant in individuals of African American ancestry with hereditary transthyretin (ATTR) amyloidosis related cardiomyopathy as it has been reported in 10% of African Americans older than age 65 with severe congestive heart failure [PMID: 28102864], and it has been deposited in ClinVar [ClinVar ID: 13426] as Pathogenic for hereditary transthyretin amyloidosis related cardiomyopathy by multiple submitters. The c.424G>A variant is observed almost exclusively in individuals of African American ancestry (~1.5% minor allele frequency) in population databases (gnomAD v2.1.1 and v3.1.2), suggesting it being a founder mutation for this population. The c.424G>A variant is located in the exon 4 of this 4-exon gene and replaces an evolutionarily conserved valine amino acid with isoleucine at position 142 of the encoded protein (p.Val142Ile) (also known as p.Val122Ile based on nomenclature for the circulating protein after N-terminal peptide cleavage) [PMIDs: 2646319, 2349941]. Functional studies demonstrated that the p.(Val142Ile) variant confer amyloidogenic properties via causing conformational changes and reducing the stability of the physiologic TTR tetramer [PMIDs: 17503405, 18276611]. Based on available evidence this c.424G>A p.Val142Ile variant identified in TTR is classified as Pathogenic. (less)
Observation 1:
Clinical Features:
Cardiomyopathy (present)
Secondary finding: yes
Observation 2:
Clinical Features:
Aortic root aneurysm (present) , Prolonged QT interval (present) , Postural tremor (present)
Secondary finding: no
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
TTR-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046214.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant is also known as p.Val122Ile by legacy nomenclature. The c.424G>A (p.Val142Ile) variant is present in the heterozygous state in the gnomAD population database … (more)
This variant is also known as p.Val122Ile by legacy nomenclature. The c.424G>A (p.Val142Ile) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (435/282792) and in the homozygous state in three individuals. It is found in approximately 3.5% of African Americans (PMID: 26123279). This variant has been identified as a causative allele for late-onset cardiac amyloidosis; specifically, it is a common cause of amyloidosis in individuals of African American ancestry with affected individuals typically presenting after the sixth decade of life (PMID: 20435197, 22877808, 24070600, 24184229). This variant has also been observed in individuals from other ancestries with a similar amyloidosis phenotype (PMID: 25846356, 22745357). Experimental studies have shown that this variant weakens the stability of TTR tetramer protein complexes in plasma and cerebrospinal fluid (PMID: 15820680, 17503405, 18276611). Based on the available evidence, c.424G>A (p.Val142Ile) is classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Transthyretin Amyloidosis
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046301.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). The c.424G>A (p.Val142Ile) … (more)
This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). The c.424G>A (p.Val142Ile) variant is present in the gnomAD population database at a frequency of 0.15% (417/277140) in the heterozygous state and a frequency of 0.001% (3/282792) in the homozygous state. The c.424G>A (p.Val142Ile) variant is found in approximately 3.5% of individuals with African American ancestry (PMID: 26123279, 34461737). This variant results in the cardiac amyloidosis phenotype (see Gene Information section for details on this specific phenotype) (PMID: 24070600, 24184229, 20435197, 22877808, 34461737). This variant has also been observed in individuals from other ancestries with a similar phenotype (PMID: 25846356, 22745357). Experimental studies have shown this variant weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). The c.424G>A (p.Val142Ile) variant affects a weakly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000616219.5
First in ClinVar: Jan 07, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant is the most common variant associated with autosomal dominant TTR-related amyloid cardiomyopathy (PMID 9017939), formerly known as familial amyloidotic cardiomyopathy (FAC); therefore the … (more)
This variant is the most common variant associated with autosomal dominant TTR-related amyloid cardiomyopathy (PMID 9017939), formerly known as familial amyloidotic cardiomyopathy (FAC); therefore the frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is also referred to as c.7356G>A (p.Val122Ile) in published literature. According to published literature, there is no reported difference in clinical presentation between individuals with this variant in the heterozygous or homozygous state (PMID: 19781421). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant results in reduced tetramer and dimer stability compared to wild-type (PMID: 17503405). (less)
|
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Pathogenic
(May 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV000902011.4
First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000284750.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). There is a small physicochemical difference between valine and isoleucine. … (more)
This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). There is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs76992529, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). It is commonly reported in individuals of African American ancestry (PMID: 20435197, 22745357, 22877808, 25846356). This variant is also known as p.Val122Ile. ClinVar contains an entry for this variant (Variation ID: 13426). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 17503405, 18276611). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806879.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Pathogenic
(Feb 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001524701.3
First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024 |
|
|
Pathogenic
(Jun 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318173.8
First in ClinVar: Oct 02, 2016 Last updated: Aug 11, 2024 |
Comment:
The c.424G>A (p.V142I) alteration (also known as p.V122I) is located in coding exon 4 of the TTR gene. This alteration results from a G to … (more)
The c.424G>A (p.V142I) alteration (also known as p.V122I) is located in coding exon 4 of the TTR gene. This alteration results from a G to A substitution at nucleotide position 424, causing the valine (V) at amino acid position 142 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.154% (435/282792) total alleles studied. The highest observed frequency was 1.622% (405/24968) of African alleles. This alteration has been reported in multiple unrelated patients with amyloid polyneuropathy (Jacobson, 1990; Jacobson, 1997; Reddi, 2014; Jacobson, 2015; Swiecicki, 2015). This is the most common TTR mutation in individuals of African descent and is also associated with familial amyloidotic cardiomyopathy (Jacobson, 1997; Arvanitis, 2017). The clinical penetrance of this mutation is age-dependent; before age sixty-five, this mutation has little or no impact on cardiac function or mortality in the majority of patients, while after age seventy, heterozygotes show a higher frequency of congestive heart failure and greater mortality with more evidence of cardiac amyloidosis than age, gender, and ethnicity-matched controls (Buxbaum, 2010). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.V142I alteration lowers the stability of the transthyretin tetramer and lowers the kinetic barrier for tetramer dissociation, which increases the extent and rate of amyloid fibril formation (Jiang, 2001). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742338.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920578.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931404.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957782.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975196.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Pathogenic
(Oct 18, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV002029170.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035782.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
Likely pathogenic
(Dec 19, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Tip-toe gait
Affected status: yes
Allele origin:
germline
|
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV004022490.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Clinical Features:
limited range of motion of upper ankle (present)
Method: Gene panel analysis
|
|
Pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: literature only
|
AMYLOIDOSIS, HEREDITARY SYSTEMIC 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034617.7
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2024 |
Comment on evidence:
Benson (2001) noted that the val122-to-ile mutation in transthyretin (V122I) was discovered in an individual with cardiomyopathy but no family history of amyloidosis (AMYLD1; 105210) … (more)
Benson (2001) noted that the val122-to-ile mutation in transthyretin (V122I) was discovered in an individual with cardiomyopathy but no family history of amyloidosis (AMYLD1; 105210) (Gorevic et al., 1989). It was first believed to explain some cases of senile cardiac amyloidosis. Both homozygous and heterozygous patients have been described. All affected individuals have been elderly, presenting after the age of 60 with cardiomyopathy, and nearly all have been African American. The mutation has been found in nearly 4% of selected African American cohorts and may be the cause of heart failure in a significant portion of the elderly in this population (Jacobson et al., 1996). Peripheral neuropathy has been reported, but is a minor clinical manifestation of this syndrome. Because transthyretin amyloidosis is an autosomal dominant trait, the high allele frequency makes this one of the most important genetic mutations in the United States. Jiang et al. (2001) stated that the V122I variant is the most common amyloidogenic variant worldwide, with an estimated 1.3 million heterozygotes. Although the age of onset (typically older than 60 years) is similar for senile systemic amyloidosis and familial amyloidotic cardiomyopathy V122I patients, the latter are much more likely to suffer cardiac failure, especially in the case of V122I homozygotes. V122I cardiac disease penetrance approaches 100%, whereas senile systemic amyloidosis, involving wildtype TTR amyloid deposition in the heart, affects less than 25% of the population above age 80. In a case of senile systemic amyloidosis in a 68-year-old black male, Jacobson et al. (1988, 1990) found an apparently homozygous substitution of isoleucine for valine at position 122 (V122I). No family members were available for study. This change predicted a genomic G-to-A transition, destroying an MaeIII restriction site. Homozygosity was established by the demonstration that the patient's DNA was entirely resistant to MaeIII cleavage. The variant was found in none of either 24 controls or 6 other patients with senile systemic amyloidosis. The only other report of homozygosity for a transthyretin mutation causing amyloidosis is the report by Holmgren et al. (1988) concerning the val30-to-met mutation (176300.0001). Gorevic et al. (1989) found that isolated amyloid fibrils from 3 cases of systemic senile amyloidosis contained subunit proteins that were transthyretin. Complete sequence analysis of 1 (presumably the same case as that studied by Jacobson et al., 1988, 1990) showed the presence of a new variant TTR molecule with a single amino acid substitution of isoleucine for valine at position 122. Thus, systemic senile amyloidosis may, in some cases at least, be a genetically determined disease expressed late in life. Snyder et al. (1989) provided evidence for the hereditary nature of senile cardiac amyloidosis. They identified 2 brothers, both homozygous for the isoleucine-for-valine substitution at position 122. The substitution predicts a guanine-to-adenine substitution at the nucleotide corresponding to the first base of codon 122 (i.e., GTC to ATC) which would result in the loss of a MaeIII restriction endonuclease recognition site. The same change was found in the DNA of the son of 1 of the brothers in heterozygous state and was confirmed by analysis of the plasma prealbumin. Westermark et al. (1990) found that the transthyretin molecule is normal in cases of the common form of senile systemic amyloidosis that affects to some degree 25% of the population over 80 years of age. For this reason they concluded that factors other than the primary structure of TTR must be important in its pathogenesis. They suggested that the cardiomyopathy that is similar to senile systemic amyloidosis and is associated with the val122-to-ile mutation represents another rare form of amyloidosis separate from the common disorder. Using PCR around codon 122 and digestion with MaeIII, Jacobson et al. (1991) investigated the frequency of the val122-to-ile mutation in 177 black persons without amyloidosis and without overt cardiac disease. The MaeIII restriction site is eliminated by the val122-to-ile mutation. They found 4 examples of the MaeIII-negative gene among 354 chromosomes, giving a frequency of 1.1% (95% confidence interval 0.32-2.7%). Thus, the variant is relatively common in blacks. HLA genotyping did not suggest that the val122-to-ile heterozygotes were of closely related genetic background. DNA testing for this variant may be useful in the clinical evaluation of black patients with unexplained cardiomyopathy. It is useful to distinguish TTR-related cardiac amyloidosis from that due to deposition of immunoglobulin light chains, AL amyloid (Olson et al., 1987). The TTR disease has a better prognosis than does AL amyloidosis involving the heart. Chemotherapy, which is thought to be beneficial in AL amyloid (Kyle et al., 1985), may be of no value in TTR-amyloidosis. With a specific test for the val122-to-ile mutation, Jacobson (1992) confirmed that the mutation was present in heterozygous state in 4 of 177 healthy black individuals and as a homozygous variant in a person with cardiac amyloidosis. He suggested that genetic testing for this mutation would be worthwhile in the evaluation of patients with unexplained cardiomyopathy. Nichols et al. (1991) had found the val122-to-ile mutation in homozygous state in anther black patient with cardiac TTR-amyloidosis, and Saraiva et al. (1990) had found it in heterozygous state in a black patient with the same disorder. After the age of 60, isolated cardiac amyloidosis is 4 times more common among blacks than whites in the United States; 3.9% of blacks are heterozygous for the amyloidogenic V122I (ile122) allele. Jacobson et al. (1997) presented evidence that a high prevalence of transthyretin ile122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. They studied cardiac tissue from 32 blacks and 20 whites over 60 years of age with isolated cardiac amyloidosis. Transthyretin amyloidosis was identified in 31 of the 32 cardiac tissue samples from the black patients and in 19 of the 20 samples from the white patients. In 6 of the 26 analyzable DNA samples (23%) from the black patients and none of the 19 samples from the white patients, heterozygosity for the ile122 variant was found. In a second, age-matched cohort of blacks without amyloidosis at the same institution, 4 of 125 DNA samples obtained at autopsy (3.2%) were heterozygous for the ile122 allele. On reexamination, the cardiac tissue from these 4 patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the ile122 variant had ventricular amyloid. Jacobson et al. (1997) concluded that the assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the ile122 allele. Benson (1997) stated that the best way to detect cardiac amyloidosis is with echocardiography. By the time a patient presents with symptoms of heart failure, the intraventricular septum and left ventricular posterior wall are thickened and the left atrium is often enlarged, an indication of the presence of restrictive cardiomyopathy of the left ventricle. Endomyocardial biopsy is also a valuable means of diagnosing cardiac amyloidosis and is recommended for patients scheduled to undergo cardiac catheterization because of a restrictive hemodynamic pattern. DNA testing is useful to confirm the hereditary nature of the disease and in counseling patients and their families. In the treatment of heart failure due to amyloidosis the avoidance of negative inotropic agents (including most antiarrhythmic medications) and overdiuresis and the maintenance of normal sinus rhythm contribute to a better outcome. Askanas et al. (2003) reported a 70-year-old African American man with sporadic inclusion body myositis (147421) and cardiac amyloidosis associated with the V122I mutation. Cultured skeletal muscle fibers from the patient showed vacuolar degeneration, congophilic inclusions, and clusters of colocalizing beta-amyloid and TTR immunoreactivities, none of which were found in normal cultured muscle fibers. Overexpression of the amyloid precursor protein gene (APP; 104760) resulted in accelerated fiber degeneration, greater congophilic inclusions, and accumulation of heavy beta-amyloid oligomers. Askanas et al. (2003) suggested that the V122I mutation may have predisposed the patient to inclusion body myositis by increasing beta-amyloid deposition in skeletal muscle. Jiang et al. (2001) demonstrated that the V122I variant, producing familial amyloidotic cardiomyopathy primarily in individuals of African descent, increases the velocity of rate-limiting tetramer dissociation, thus resulting in accelerated amyloidogenesis. Chakrabartty (2001) pointed out that the in vitro studies of Jiang et al. (2001) provided a biophysical explanation of how disease-associated mutations in TTR affect the course of TTR amyloidoses, thus strengthening the amyloid hypothesis. In 2 Afro-Caribbean patients with cardiac amyloidosis, aged 63 and 74 years, respectively, Lachmann et al. (2002) identified heterozygosity for the V122I mutation in the TTR gene. Cardiomyopathy was the predominant clinical feature in both patients, and 1 of them also displayed neuropathy. To assess the effect of the V122I variant on long-term morbidity and mortality, Quarta et al. (2015) genotyped 3,856 black participants in the Atherosclerosis Risk in Communities study and assessed cardiac structure and function as well as features suggestive of cardiac amyloidosis in participants older than 65 years of age. The authors identified carrier status for the V122I variant in 124 participants (3%). After 21.5 years of follow-up, Quarta et al. (2015) did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1,382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval, 0.73-1.36; p = 0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% confidence interval, 1.03-2.10; p = 0.04). On echocardiography at visit 5, carriers had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers, although carriers had a low prevalence of overt manifestations of amyloid cardiomyopathy. Quarta et al. (2015) did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasted with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. Buxbaum and Ruberg (2017) reviewed the TTR V122I allele. The frequency of this amyloidogenic allele is 0.0173, and it is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicated that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. Genotyping of tissues from 112 consecutive autopsies of African Americans age 65 or over identified 4 samples (3.9%) positive for the V122I allele; heart tissues from all 4 carriers showed some degree of cardiac amyloid deposition. However, the clinical penetrance varied, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. The authors reported potential forms of therapy in clinical trials and suggested testing for this variant in older African Americans with heart disease. (less)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809425.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Amyloidosis, hereditary, transthyretin-related
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142480.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000371.3:c.424G>A (p.Val142Ile) was reported as Val122Ile in the TTR gene, and it has an allele frequency of 0.016 in African subpopulation in the gnomAD database. … (more)
NM_000371.3:c.424G>A (p.Val142Ile) was reported as Val122Ile in the TTR gene, and it has an allele frequency of 0.016 in African subpopulation in the gnomAD database. Functional studies demonstrate that Val122Ile affect TTR protein function (PMID: 18276611). V122I variant is the most common amyloidogenic mutation worldwide, associated with familial amyloidotic cardiomyopathy in individuals of African descent. It is estimated that 4% of African Americans are heterozygous for the V122I variant, with an age of onset at around 60 years of age (PMID: 18276611). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3 (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749428.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 06-01-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 06-01-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of heart disease (present)
Indication for testing: Presymptomatic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-06-01
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary Transthyretin Amyloidosis. | Adam MP | - | 2024 | PMID: 20301373 |
Amyloidogenicity assessment of transthyretin gene variants. | Grether NB | Annals of clinical and translational neurology | 2022 | PMID: 35903975 |
Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals. | Parcha V | JAMA | 2022 | PMID: 35377943 |
Transthyretin V142I Genetic Variant and Cardiac Remodeling, Injury, and Heart Failure Risk in Black Adults. | Coniglio AC | JACC. Heart failure | 2022 | PMID: 35115086 |
Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS). | Damy T | European heart journal | 2022 | PMID: 30938420 |
Phenotypic Spectrum of Transthyretin Cardiac Amyloidosis in a Family: Impact of Mutation Zygosity and Sex. | Tushak ZJ | JACC. CardioOncology | 2021 | PMID: 34729535 |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry. | Parker MM | Scientific reports | 2021 | PMID: 34079032 |
Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis. | Soper ER | Journal of personalized medicine | 2021 | PMID: 33467513 |
Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. | Auer-Grumbach M | Journal of clinical medicine | 2020 | PMID: 32674397 |
The mutational constraint spectrum quantified from variation in 141,456 humans. | Karczewski KJ | Nature | 2020 | PMID: 32461654 |
Genetic Testing for Diagnosis of Hypertrophic Cardiomyopathy Mimics: Yield and Clinical Significance. | Hoss S | Circulation. Genomic and precision medicine | 2020 | PMID: 32150461 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Diagnosis of genetic amyloidosis through the analysis of transthyretin gene mutation using high-resolution melting. | Lahuerta C | International journal of cardiology | 2020 | PMID: 31740141 |
Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy. | Maurizi N | International journal of cardiology | 2020 | PMID: 31371117 |
Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. | Damrauer SM | JAMA | 2019 | PMID: 31821430 |
Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses. | De Lillo A | Human genetics | 2019 | PMID: 31659433 |
Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy. | Lopes LR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2019 | PMID: 31554435 |
Cardiac amyloidosis: the need for early diagnosis. | Oerlemans MIFJ | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 31359320 |
Transthyretin Amyloidosis Presenting With Upper-Extremity Neuropathy and Paucity of Autonomic Impairment. | Devarapalli S | Journal of clinical neuromuscular disease | 2019 | PMID: 31135624 |
Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants. | Polimanti R | Journal of clinical medicine | 2019 | PMID: 30813263 |
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. | Ji J | Cold Spring Harbor molecular case studies | 2019 | PMID: 30755392 |
A Patient With Hereditary ATTR and a Novel AGel p.Ala578Pro Amyloidosis. | Sridharan M | Mayo Clinic proceedings | 2018 | PMID: 30093168 |
Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion. | Sheikh N | Circulation | 2018 | PMID: 29764897 |
The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population. | Lavigne-Moreira C | Journal of the peripheral nervous system : JPNS | 2018 | PMID: 29520877 |
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
Prevalence of mutant ATTR cardiac amyloidosis in elderly African Americans with heart failure. | Arvanitis M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2017 | PMID: 29052438 |
Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. | Iorio A | European journal of human genetics : EJHG | 2017 | PMID: 28635949 |
Transthyretin amyloidosis: a phenocopy of hypertrophic cardiomyopathy. | Vermeer AMC | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2017 | PMID: 28475415 |
Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. | Buxbaum JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28102864 |
Phenotypic variability of TTR Val122Ile mutation: a Caucasian patient with axonal neuropathy and normal heart. | Stancanelli C | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2017 | PMID: 27838833 |
Novel Antibody for the Treatment of Transthyretin Amyloidosis. | Hosoi A | The Journal of biological chemistry | 2016 | PMID: 27758856 |
Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells. | Chen JJ | Cell chemical biology | 2016 | PMID: 27720586 |
The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. | Jacobson DR | Molecular genetics & genomic medicine | 2016 | PMID: 27652282 |
Afro-Caribbean Heart Failure in the United Kingdom: Cause, Outcomes, and ATTR V122I Cardiac Amyloidosis. | Dungu JN | Circulation. Heart failure | 2016 | PMID: 27618855 |
Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). | Maurer MS | Journal of the American College of Cardiology | 2016 | PMID: 27386769 |
Transthyretin Cardiac Amyloidosis in Black Americans. | Shah KB | Circulation. Heart failure | 2016 | PMID: 27188913 |
Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. | Damy T | European heart journal | 2016 | PMID: 26537620 |
The Val142Ile transthyretin cardiac amyloidosis: not only an Afro-American pathogenic variant? A single-centre Italian experience. | Cappelli F | Journal of cardiovascular medicine (Hagerstown, Md.) | 2016 | PMID: 26428663 |
Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. | Jacobson DR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2015 | PMID: 26123279 |
Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. | Swiecicki PL | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2015 | PMID: 26017327 |
(99m)Tc-HMDP scintigraphy rectifies wrong diagnosis of AL amyloidosis. | Galat A | Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology | 2015 | PMID: 26002815 |
Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. | Fontana M | Radiology | 2015 | PMID: 25997029 |
The Val142Ile transthyretin cardiac amyloidosis: more than an Afro-American pathogenic variant. | Perfetto F | Journal of community hospital internal medicine perspectives | 2015 | PMID: 25846356 |
Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy. | Carr AS | Neuromuscular disorders : NMD | 2015 | PMID: 25819286 |
The amyloidogenic V122I transthyretin variant in elderly black Americans. | Quarta CC | The New England journal of medicine | 2015 | PMID: 25551524 |
Amyloidogenic and non-amyloidogenic transthyretin variants interact differently with human cardiomyocytes: insights into early events of non-fibrillar tissue damage. | Manral P | Bioscience reports | 2015 | PMID: 25395306 |
Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis. | Thenappan T | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 24818650 |
An Afro-Caribbean patient with a thick heart. | Dubrey SW | QJM : monthly journal of the Association of Physicians | 2014 | PMID: 24633258 |
A compound T60A and V122I heterozygosity in the transthyretin gene causing early onset severe cardiac amyloidosis. | Liu YC | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 24517438 |
Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis. | Mangione PP | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 24474780 |
Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life. | Reddi HV | The Journal of molecular diagnostics : JMD | 2014 | PMID: 24184229 |
Genotype, echocardiography, and survival in familial transthyretin amyloidosis. | Arruda-Olson AM | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 24131106 |
Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. | Dohrn MF | Journal of neurology | 2013 | PMID: 24101130 |
Comparison of cardiac amyloidosis due to wild-type and V122I transthyretin in older adults referred to an academic medical center. | Givens RC | Aging health | 2013 | PMID: 24073013 |
Familial amyloid polyneuropathy. | Barreiros AP | Digestive diseases (Basel, Switzerland) | 2013 | PMID: 23797140 |
AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. | Penchala SC | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23716704 |
Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. | Ihse E | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23713495 |
THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. | Coelho T | Current medical research and opinion | 2013 | PMID: 23193944 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. | Rapezzi C | European heart journal | 2013 | PMID: 22745357 |
Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). | Ruberg FL | American heart journal | 2012 | PMID: 22877808 |
Aged vervet monkeys developing transthyretin amyloidosis with the human disease-causing Ile122 allele: a valid pathological model of the human disease. | Ueda M | Laboratory investigation; a journal of technical methods and pathology | 2012 | PMID: 22184092 |
Coexistent asymptomatic myeloma and hereditary cardiac amyloidosis: an unusual case of heart failure. | Lee L | British journal of hospital medicine (London, England : 2005) | 2011 | PMID: 22083004 |
Relation of clinical, echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of the transthyretin V122I allele in older African-American men. | Jacobson D | The American journal of cardiology | 2011 | PMID: 21600538 |
A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. | Buxbaum J | American heart journal | 2010 | PMID: 20435197 |
Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. | Connors LH | American heart journal | 2009 | PMID: 19781421 |
Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid. | Eriksson M | The American journal of surgical pathology | 2009 | PMID: 18830126 |
Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. | Hamour IM | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | 2008 | PMID: 18318779 |
Different disease-causing mutations in transthyretin trigger the same conformational conversion. | Steward RE | Protein engineering, design & selection : PEDS | 2008 | PMID: 18276611 |
Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. | Gripp KW | American journal of medical genetics. Part A | 2007 | PMID: 17551924 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Homozygous transthyretin mutation in an African American Male. | Jacob EK | The Journal of molecular diagnostics : JMD | 2007 | PMID: 17251346 |
Influence of proteinuria on cardiovascular risk and response to angiotensin-converting enzyme inhibition after myocardial infarction. | Jose P | Journal of the American College of Cardiology | 2006 | PMID: 16631015 |
Transthyretin V122I in African Americans with congestive heart failure. | Buxbaum J | Journal of the American College of Cardiology | 2006 | PMID: 16631014 |
Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
Inclusion-body myositis: clinical, diagnostic, and pathologic aspects. | Engel WK | Neurology | 2006 | PMID: 16432141 |
A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. | Yamashita T | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2005 | PMID: 16011990 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
The hereditary amyloidoses. | Benson MD | Best practice & research. Clinical rheumatology | 2003 | PMID: 15123043 |
Tabulation of human transthyretin (TTR) variants, 2003. | Connors LH | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14640030 |
Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging. | Askanas V | Current opinion in rheumatology | 2003 | PMID: 14569203 |
Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. | Askanas V | Neurology | 2003 | PMID: 12874414 |
Medical errors on an inpatient neurology service. | Frank S | Neurology | 2003 | PMID: 12874413 |
Newest pathogenetic considerations in inclusion-body myositis: possible role of amyloid-beta, cholesterol, relation to aging and to Alzheimer's disease. | Askanas V | Current rheumatology reports | 2002 | PMID: 12217248 |
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. | Lachmann HJ | The New England journal of medicine | 2002 | PMID: 12050338 |
The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. | Jiang X | Proceedings of the National Academy of Sciences of the United States of America | 2001 | PMID: 11752443 |
Progress in transthyretin fibrillogenesis research strengthens the amyloid hypothesis. | Chakrabartty A | Proceedings of the National Academy of Sciences of the United States of America | 2001 | PMID: 11752419 |
Transthyretin mutations in hyperthyroxinemia and amyloid diseases. | Saraiva MJ | Human mutation | 2001 | PMID: 11385707 |
Transthyretin isoleucine-122 mutation in African and American blacks. | Afolabi I | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2000 | PMID: 10842715 |
Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele. | Askanas V | Annals of neurology | 2000 | PMID: 10762172 |
A new amyloidogenic transthyretin variant (Val122Ala) found in a compound heterozygous patient. | Théberge R | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1999 | PMID: 10211412 |
Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. | Jacobson DR | The New England journal of medicine | 1997 | PMID: 9017939 |
Revised transthyretin Ile 122 allele frequency in African-Americans. | Jacobson DR | Human genetics | 1996 | PMID: 8698351 |
Transthyretin Ser 6 gene frequency in individuals without amyloidosis. | Jacobson DR | Human genetics | 1995 | PMID: 7868124 |
Transthyretin Pro 36 associated with familial amyloidotic polyneuropathy in an Ashkenazic Jewish kindred. | Jacobson DR | Human genetics | 1992 | PMID: 1358785 |
Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. | Jacobson DR | Human genetics | 1992 | PMID: 1351039 |
Frequency and genetic background of the position 122 (Val----Ile) variant transthyretin gene in the black population. | Jacobson DR | American journal of human genetics | 1991 | PMID: 2063870 |
Senile cardiac amyloidosis associated with homozygosity for a transthyretin variant (ILE-122). | Nichols WC | The Journal of laboratory and clinical medicine | 1991 | PMID: 2002274 |
A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90. | Skare JC | Clinical genetics | 1991 | PMID: 1997217 |
A homozygous transthyretin variant associated with senile systemic amyloidosis: evidence for a late-onset disease of genetic etiology. | Jacobson DR | American journal of human genetics | 1990 | PMID: 2349941 |
Fibril in senile systemic amyloidosis is derived from normal transthyretin. | Westermark P | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2320592 |
Cardiac amyloidosis: report of a patient heterozygous for the transthyretin isoleucine 122 variant. | Saraiva MJ | Scandinavian journal of immunology | 1990 | PMID: 2237288 |
Systemic senile amyloidosis. Identification of a new prealbumin (transthyretin) variant in cardiac tissue: immunologic and biochemical similarity to one form of familial amyloidotic polyneuropathy. | Gorevic PD | The Journal of clinical investigation | 1989 | PMID: 2646319 |
A new mutation causing familial amyloidotic polyneuropathy. | Skare JC | Biochemical and biophysical research communications | 1989 | PMID: 2590199 |
Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy. | Holmgren G | Clinical genetics | 1988 | PMID: 3229002 |
Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. | Olson LJ | The New England journal of medicine | 1987 | PMID: 3627183 |
Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy. Appalachian amyloid. | Benson MD | Arthritis and rheumatism | 1987 | PMID: 3030336 |
Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine. | Kyle RA | The American journal of medicine | 1985 | PMID: 3934968 |
Benson, M. D. Characterization of an amyloid fibril protein in heredofamilial amyloidosis. (Abstract) Clin. Res. 28: 340A, 1980. | - | - | - | - |
Buxbaum, J. N. Personal Communication. 1987. New York, N. Y. | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTR | - | - | - | - |
Snyder, E. L., Nichols, W. C., Liepnieks, J. J., Benson, M. D. Direct evidence for the hereditary nature of senile cardiac (systemic) amyloidosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A220, 1989. | - | - | - | - |
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Text-mined citations for rs76992529 ...
HelpRecord last updated Sep 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.