ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.149T>C (p.Val50Ala)
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_000371.4(TTR):c.149T>C (p.Val50Ala)
Variation ID: 13430 Accession: VCV000013430.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592975 (GRCh38) [ NCBI UCSC ] 18: 29172938 (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 Aug 29, 2016 Feb 14, 2024 Sep 18, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.149T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Val50Ala missense NC_000018.10:g.31592975T>C NC_000018.9:g.29172938T>C NG_009490.1:g.6209T>C LRG_416:g.6209T>C LRG_416t1:c.149T>C LRG_416p1:p.Val50Ala P02766:p.Val50Ala - Protein change
- V50A
- Other names
- V30A
- Canonical SPDI
- NC_000018.10:31592974:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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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 |
369 | 416 |
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
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 18, 2021 | RCV000014372.30 |
Submissions - Germline
Classification
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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
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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
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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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Pathogenic
(Sep 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002113129.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22620962, 22745357, … (more)
This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22620962, 22745357, 23833285, 24455802, 24555660, 26115788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TTR protein function (PMID: 23523753). 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. ClinVar contains an entry for this variant (Variation ID: 13430). This variant is also known as Val30Ala. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1544214, 12757474, 17503405, 22745357, 26521788). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 50 of the TTR protein (p.Val50Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Amyloidogenic transthyretin amyloidosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363571.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TTR c.149T>C (p.Val50Ala) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Three … (more)
Variant summary: TTR c.149T>C (p.Val50Ala) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). c.149T>C has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (e.g. Liu_2017, Meng_2015, Nepomuceno_2004, Suhr_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggest that the variant promotes the formation of unfolded monomers and amyloid fibrils, which potentially contribute to increased neurotoxicity and pathology (Zhang_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 01, 1992)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034621.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
Jones et al. (1990, 1992) showed that a dominantly inherited amyloid polyneuropathy (105210) in a family of German descent was due to a cytosine for … (more)
Jones et al. (1990, 1992) showed that a dominantly inherited amyloid polyneuropathy (105210) in a family of German descent was due to a cytosine for thymine substitution in the second base of codon 30, resulting in substitution of alanine for valine (V30A). This mutation created a novel CfoI restriction endonuclease site in exon 2. This represented a hydrophilic substitution at a hydrophobic core position. The change is in the same codon as the val30-to-met mutation found in the Andrade or Portuguese type (176300.0001); see also the val30-to-leu mutation (176300.0024). (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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Hereditary Transthyretin Amyloidosis. | Adam MP | - | 2021 | PMID: 20301373 |
Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds. | Liu G | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 27859927 |
Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. | Suhr OB | Transplantation | 2016 | PMID: 26656838 |
Hereditary Transthyretin Amyloidosis in Eight Chinese Families. | Meng LC | Chinese medical journal | 2015 | PMID: 26521788 |
Three Turkish families with different transthyretin mutations. | Bekircan-Kurt CE | Neuromuscular disorders : NMD | 2015 | PMID: 26115788 |
Frequency of the transthyretin Val30Met mutation in the northern Swedish population. | Olsson M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 24555660 |
Unexplained cardiac failure leading to the identification of a Belgian family affected by hereditary amyloidosis. | De Pasqual A | Acta clinica Belgica | 2013 | PMID: 24455802 |
Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy. | Coutinho MC | Circulation. Cardiovascular imaging | 2013 | PMID: 23833285 |
The impact of V30A mutation on transthyretin protein structural stability and cytotoxicity against neuroblastoma cells. | Zhang F | Archives of biochemistry and biophysics | 2013 | PMID: 23523753 |
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 |
Genotype--phenotype correlation in FAP. | Zeldenrust SR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 22620962 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Detection of genetic variants of transthyretin by liquid chromatography-dual electrospray ionization fourier-transform ion-cyclotron-resonance mass spectrometry. | Nepomuceno AI | Clinical chemistry | 2004 | PMID: 15205369 |
Genetics of familial amyloidotic polyneuropathy in a Hong Kong Chinese kindred. | Mak CM | Acta neurologica Scandinavica | 2003 | PMID: 12757474 |
Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent. | Jones LA | Clinical genetics | 1992 | PMID: 1544214 |
Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. | Jones LA | American journal of human genetics | 1991 | PMID: 1850191 |
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Text-mined citations for rs79977247 ...
HelpRecord last updated Mar 23, 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.