VCV000013451.4 - ClinVar

NM_000371.4(TTR):c.200G>C (p.Gly67Ala)

Germline

Classification

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.

(4)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000371.4(TTR):c.200G>C (p.Gly67Ala)

Variation ID: 13451 Accession: VCV000013451.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31593026 (GRCh38) [ NCBI UCSC ] 18: 29172989 (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	May 26, 2024	Dec 29, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000371.4:c.200G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000362.1:p.Gly67Ala	missense
NC_000018.10:g.31593026G>C
NC_000018.9:g.29172989G>C
NG_009490.1:g.6260G>C
LRG_416:g.6260G>C
LRG_416t1:c.200G>C	LRG_416p1:p.Gly67Ala
	P02766:p.Gly67Ala

... more HGVS ... less HGVS

Protein change

G67A

Other names

G47A

Canonical SPDI

NC_000018.10:31593025:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA256845 UniProtKB: P02766#VAR_007561 OMIM: 176300.0035 dbSNP: rs121918090 VarSome

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
Gene	OMIM	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.
TTR		-	-	GRCh38 GRCh37	374	421

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.
Amyloidosis, hereditary systemic 1	Pathogenic (2)	criteria provided, single submitter	Feb 15, 2017	RCV000014393.25
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 31, 2016	RCV000516227.2
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 29, 2021	RCV002415416.2

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.
Pathogenic (Mar 31, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000616209.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (10) PubMed: 12440483‚ 21550574‚ 24101373‚ 12557758‚ 19752327‚ 7951260‚ 17503405‚ 24053266‚ 22745357‚ 10845569
Pathogenic (Feb 15, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Amyloidosis, hereditary systemic 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696617.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (4) PubMed: 27584576‚ 15123043‚ 17503405‚ 22745357 Comment: Variant summary: The TTR c.200G>C (p.Gly67Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution … (more) Variant summary: The TTR c.200G>C (p.Gly67Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121408 control chromosomes but was reported in several patients suggesting causality. Moreover, in at least two families the variant was observed to co-segregate with the disease further supporting a pathogenic outcome. Different variants affecting the same codon are listed in HGMD/ClinVar with a casual classification indicating the variant to be located in a mutational hotspot which supports the clinical relevance of the Gly67 residue. In addition, the p.Gly67Ala is found worldwide and has a high prevalence in German familial amyloid polyneuropathy patients (Niemietz_PlosOne_2016). Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 29, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002722874.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 10677864‚ 10845569‚ 22745357‚ 24053266‚ 7951260 Comment: The p.G67A pathogenic mutation (also known as c.200G>C), located in coding exon 2 of the TTR gene, results from a G to C substitution at … (more) The p.G67A pathogenic mutation (also known as c.200G>C), located in coding exon 2 of the TTR gene, results from a G to C substitution at nucleotide position 200. The amino acid change results in glycine to alanine at codon 67, an amino acid with similar properties. This mutation, which is also known as p.G47A, was first reported in two unrelated Italian families with transthyretin (TTR) amyloidosis; both families presented with peripheral neuropathy and cardiomyopathy (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Ferlini A et al. Clin. Genet., 2000 Apr;57:284-90). In a large cohort of families with TTR amyloidosis, this mutation was identified in 7 individuals from 2 unrelated families; 4 of these individuals had a mixed cardiac and neurologic phenotype and 3 of these individuals only had neurologic phenotype (Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Apr 01, 2000)	no assertion criteria provided Method: literature only	AMYLOIDOSIS, HEREDITARY SYSTEMIC 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034642.2 First in ClinVar: Apr 04, 2013 Last updated: May 26, 2024	Publications: PubMed (2) PubMed: 7951260‚ 10845569 Comment on evidence: In a family originating from Abruzzi, Italy, Ferlini et al. (1994) described amyloid polyneuropathy and cardiomyopathy (AMYLD1; 105210) in members of 3 generations caused by … (more) In a family originating from Abruzzi, Italy, Ferlini et al. (1994) described amyloid polyneuropathy and cardiomyopathy (AMYLD1; 105210) in members of 3 generations caused by a substitution of the second nucleotide of codon 47 of transthyretin, which caused a change from glycine to alanine (G47A). A substitution in the first nucleotide of codon 47 had been found as the cause of a gly47-to-arg mutation (G47R; 176300.0020). Ferlini et al. (2000) described another Italian family with the glycine-to-alanine substitution caused by a G-to-C transversion in the penultimate nucleotide of codon 47. The proband was a 61-year-old woman originating from Tuscany. She presented with a 4-year history of weakness, exercise dyspnea, peripheral edema, and progressive weight loss. Left carpal tunnel surgery had been performed at the age of 56 years. Abdominal fat biopsy showed amyloid deposits. Echocardiography showed restrictive cardiomyopathy with a concentrically thickened left ventricle and reduced ejection fraction. (less)

Comment:

Variant summary: The TTR c.200G>C (p.Gly67Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121408 control chromosomes but was reported in several patients suggesting causality. Moreover, in at least two families the variant was observed to co-segregate with the disease further supporting a pathogenic outcome. Different variants affecting the same codon are listed in HGMD/ClinVar with a casual classification indicating the variant to be located in a mutational hotspot which supports the clinical relevance of the Gly67 residue. In addition, the p.Gly67Ala is found worldwide and has a high prevalence in German familial amyloid polyneuropathy patients (Niemietz_PlosOne_2016). Taken together, this variant is classified as pathogenic.

Comment:

The p.G67A pathogenic mutation (also known as c.200G>C), located in coding exon 2 of the TTR gene, results from a G to C substitution at nucleotide position 200. The amino acid change results in glycine to alanine at codon 67, an amino acid with similar properties. This mutation, which is also known as p.G47A, was first reported in two unrelated Italian families with transthyretin (TTR) amyloidosis; both families presented with peripheral neuropathy and cardiomyopathy (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Ferlini A et al. Clin. Genet., 2000 Apr;57:284-90). In a large cohort of families with TTR amyloidosis, this mutation was identified in 7 individuals from 2 unrelated families; 4 of these individuals had a mixed cardiac and neurologic phenotype and 3 of these individuals only had neurologic phenotype (Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Evaluation of Therapeutic Oligonucleotides for Familial Amyloid Polyneuropathy in Patient-Derived Hepatocyte-Like Cells.	Niemietz CJ	PloS one	2016	PMID: 27584576
Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.	Merlini G	Journal of cardiovascular translational research	2013	PMID: 24101373
Description of transthyretin S50A, S52P and G47A mutations in familial amyloidosis polyneuropathy.	González-Duarte A	Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis	2013	PMID: 24053266
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
Rate of progression of transthyretin amyloidosis.	Benson MD	The American journal of cardiology	2011	PMID: 21550574
Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.	Rapezzi C	Circulation	2009	PMID: 19752327
Genetic microheterogeneity of human transthyretin detected by IEF.	Altland K	Electrophoresis	2007	PMID: 17503405
The hereditary amyloidoses.	Benson MD	Best practice & research. Clinical rheumatology	2003	PMID: 15123043
Transthyretin mutation (TTRGly47Ala) associated with familial amyloid polyneuropathy in a French family.	Magy N	Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis	2002	PMID: 12557758
Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis.	Arbustini E	Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis	2002	PMID: 12440483
Mutation and transcription analysis of transthyretin gene in Italian families with hereditary amyloidosis: a putative novel hot spot' in codon 47.	Ferlini A	Clinical genetics	2000	PMID: 10845569
An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy.	Solaro C	Neuromuscular disorders : NMD	2000	PMID: 10677864
A new mutation (TTR Ala-47) in the transthyretin gene associated with hereditary amyloidosis.	Ferlini A	Human mutation	1994	PMID: 7951260
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Text-mined citations for rs121918090 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000371.4(TTR):c.200G>C (p.Gly67Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918090 ...