ClinVar Genomic variation as it relates to human health
NM_000477.7(ALB):c.725G>A (p.Arg242His)
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
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NM_000477.7(ALB):c.725G>A (p.Arg242His)
Variation ID: 18225 Accession: VCV000018225.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q13.3 4: 73412007 (GRCh38) [ NCBI UCSC ] 4: 74277724 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 16, 2014 Jun 9, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000477.7:c.725G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000468.1:p.Arg242His missense NC_000004.12:g.73412007G>A NC_000004.11:g.74277724G>A NG_009291.1:g.12753G>A P02768:p.Arg242His - Protein change
- R242H
- Other names
- R218H
- Canonical SPDI
- NC_000004.12:73412006: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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0.00040 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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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ALB | - | - |
GRCh38 GRCh37 |
170 | 196 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 18, 2016 | RCV000019886.35 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2023 | RCV001753423.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV003398549.1 |
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
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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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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Hyperthyroxinemia, familial dysalbuminemic
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267207.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Uncertain significance
(Apr 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001986354.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in many patients with familial dysalbuminemic hyperthyroxinemia (Petersen et al., 1994; Choudhary et al., 2015; Cho et al., 2017; Khoo et al., 2020); Also … (more)
Reported in many patients with familial dysalbuminemic hyperthyroxinemia (Petersen et al., 1994; Choudhary et al., 2015; Cho et al., 2017; Khoo et al., 2020); Also reported as R218H due to alternate nomenclature; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26522458, 30027432, 9329347, 11743520, 27834068, 24646103, 24494774, 8048949, 12743361, 19723509, 25153218, 28781323, 26169058, 29676214, 32101523, 30197844, 29133890, 8064810, 12099390) (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Hyperthyroxinemia, familial dysalbuminemic
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013589.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Same nucleotide change resulting in same amino … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ALB related disorder (Also known as Arg218His. PMID: 8048949). Different missense changes at the same codon (p.Arg242Pro, p.Arg242Ser) have been reported to be associated with ALB related disorder (ClinVar ID: VCV000018238 / PMID: 24494774, 9329347). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Euthyroid hyperthyroxinemia (present)
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Uncertain significance
(Oct 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122526.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: ALB c.725G>A (p.Arg242His) results in a non-conservative amino acid change located in the Serum albumin, N-terminal (IPR014760) of the encoded protein sequence. Four … (more)
Variant summary: ALB c.725G>A (p.Arg242His) results in a non-conservative amino acid change located in the Serum albumin, N-terminal (IPR014760) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALB causing Analbuminemia (7.2e-05 vs ND), allowing no conclusion about variant significance. c.725G>A has been reported in the literature in individuals affected with Dysalbuminaemic hyperthyroxinaemia (e.g. Cho_2017, Ryan_2016, Sunthornthepvarakul_1994, Petersen_1994) . These reports do not provide unequivocal conclusions about association of the variant with Analbuminemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27834068, 8064810, 26169058, 8048949). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003251568.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects ALB function (PMID: 12743361). 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 not expected to disrupt ALB protein function. ClinVar contains an entry for this variant (Variation ID: 18225). This variant is also known as R218H. This missense change has been observed in individual(s) with dysalbuminemic hyperthyroxinemia (PMID: 8048949, 12099390, 26169058, 29676214, 33728390). This variant is present in population databases (rs75002628, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the ALB protein (p.Arg242His). (less)
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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HYPERTHYROXINEMIA, FAMILIAL DYSALBUMINEMIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040184.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 2 unrelated patients with dysalbuminemic hyperthyroxinemia (FDAH; 615999), Petersen et al. (1994) identified an arg218-to-his substitution that was caused by a G (CGC)-to-A (CAG) … (more)
In 2 unrelated patients with dysalbuminemic hyperthyroxinemia (FDAH; 615999), Petersen et al. (1994) identified an arg218-to-his substitution that was caused by a G (CGC)-to-A (CAG) transition at nucleotide 653 in the ALB gene. Abnormal affinity of the albumin from these patients for a thyroxine analog was verified by an adaptation of the procedure used in routine free T4 measurement. Both subjects were heterozygous. During the preparation of the manuscript, a third patient with the same mutation was found, suggesting that R218H may be the most frequent cause of this disorder. The mutation created a new HphI restriction site in exon 7, which was used diagnostically. Sunthornthepvarakul et al. (1994) identified R218H mutation in affected members of 8 unrelated families with dysalbuminemic hyperthyroxinemia. Pohlenz et al. (2001) reported a 5-month-old boy with familial dysalbuminemic hyperthyroxinemia and congenital hypothyroidism who had a blood thyrotropin (TSH) level of 479 mU/L but normal T4 and elevated T3 levels. The patient and his euthyroid father and brother all carried the R218H mutation. (less)
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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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Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests. | Ting MJM | Journal of the Endocrine Society | 2021 | PMID: 33728390 |
Homozygous Mutation in Human Serum Albumin and Its Implication on Thyroid Tests. | Mimoto MS | Thyroid : official journal of the American Thyroid Association | 2018 | PMID: 29676214 |
First Report of Familial Dysalbuminemic Hyperthyroxinemia With an ALB Variant. | Cho YY | Annals of laboratory medicine | 2017 | PMID: 27834068 |
Familial dysalbuminaemic hyperthyroxinaemia: a rapid and novel mass spectrometry approach to diagnosis. | Ryan JB | Annals of clinical biochemistry | 2016 | PMID: 26169058 |
A novel mutation in the Albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction. | Greenberg SM | Thyroid : official journal of the American Thyroid Association | 2014 | PMID: 24494774 |
Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia. | Petitpas I | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12743361 |
Familial dysalbuminemic hyperthyroxinemia: a rare example of albumin polymorphism and its rapid molecular diagnosis. | AvRuskin TW | Journal of pediatric endocrinology & metabolism : JPEM | 2002 | PMID: 12099390 |
Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene. | Pohlenz J | The Journal of pediatrics | 2001 | PMID: 11743520 |
A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred. | Wada N | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9329347 |
A point mutation in the human serum albumin gene results in familial dysalbuminaemic hyperthyroxinaemia. | Petersen CE | Journal of medical genetics | 1994 | PMID: 8064810 |
An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families. | Sunthornthepvarakul T | Biochemical and biophysical research communications | 1994 | PMID: 8048949 |
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Text-mined citations for rs75002628 ...
HelpRecord last updated Jun 10, 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.