ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.148G>C (p.Val50Leu)
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.148G>C (p.Val50Leu)
Variation ID: 13440 Accession: VCV000013440.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q12.1 18: 31592974 (GRCh38) [ NCBI UCSC ] 18: 29172937 (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 Feb 14, 2024 Sep 5, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000371.4:c.148G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Val50Leu missense NC_000018.10:g.31592974G>C NC_000018.9:g.29172937G>C NG_009490.1:g.6208G>C LRG_416:g.6208G>C LRG_416t1:c.148G>C LRG_416p1:p.Val50Leu P02766:p.Val50Leu - Protein change
- V50L
- Other names
- V30L
- Canonical SPDI
- NC_000018.10:31592973:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
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 |
369 | 413 |
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 (2) |
criteria provided, single submitter
|
Sep 5, 2021 | RCV000014382.28 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001173291.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 17, 2019 | RCV002390107.1 |
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
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
(-)
|
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: SCV001336375.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
|
|
Pathogenic
(Sep 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002127487.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. 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: 1544214, 22620962, 23523753, 23833285, 24555660, 26521788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 13440). This variant is also known as Val30Leu. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1520326). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 50 of the TTR protein (p.Val50Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. (less)
|
|
Pathogenic
(Sep 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002700893.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.V50L pathogenic mutation (also known as c.148G>C and V30L), located in coding exon 2 of the TTR gene, results from a G to C … (more)
The p.V50L pathogenic mutation (also known as c.148G>C and V30L), located in coding exon 2 of the TTR gene, results from a G to C substitution at nucleotide position 148. The valine at codon 50 is replaced by leucine, an amino acid with highly similar properties.The p.V50L mutation (c.148G>C and c.148G>T) has been reported in multiple individuals with TTR amyloidosis (Utsugisawa K et al. Muscle Nerve, 1998 Dec;21:1783-5; Mitsuhashi S et al. Amyloid, 2005 Dec;12:216-25; Suhr OB et al. Amyloid, 2009 Dec;16:208-14; Nakagawa M et al. Amyloid, 2013 Jun;20:138-40), and was identified in two distant affected relatives in a large family with incomplete penetrance (Chen H et al. Sci Rep, 2016 05;6:26362). This variant was not reported in the gnomAD database, with coverage at this position. A disease-causing mutation, p.V50M, has been described in the same codon (Soares ML et al. Eur. J. Hum. Genet., 2004 Mar;12:225-377). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 01, 1998)
|
no assertion criteria provided
Method: literature only
|
AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034631.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a Japanese patient with familial amyloid polyneuropathy (105210), Murakami et al. (1992) used single-strand conformation polymorphism analysis and sequence analysis of PCR-amplified exons of … (more)
In a Japanese patient with familial amyloid polyneuropathy (105210), Murakami et al. (1992) used single-strand conformation polymorphism analysis and sequence analysis of PCR-amplified exons of TTR to demonstrate a val30-to-leu (V30L) mutation. The mutation created a Cfr13I site. 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-ala mutation (176300.0014). The pathogenic significance of the V30L mutation was confirmed by Utsugisawa et al. (1998), who demonstrated the same mutation in 3 members of a Japanese family with type I FAP. The proband was a 46-year-old woman who gradually developed sensory dullness, muscle weakness, and atrophy of the legs and the arms. The pupils were dilated and did not react to light and accommodation, but were hypersensitive to both 0.1% pilocarpine and 0.125% epinephrine. Tendon reflexes were absent or diminished in the extremities. She showed severe hypesthesia in the distal parts of the extremities, but sparing joint sensation. Orthostatic hypotension was demonstrated with no change in pulse rate on assuming the standing position. Her father died at age 53 years, having had similar symptoms. (less)
|
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 |
---|---|---|---|---|
Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy. | Chen H | Scientific reports | 2016 | PMID: 27212199 |
Hereditary Transthyretin Amyloidosis in Eight Chinese Families. | Meng LC | Chinese medical journal | 2015 | PMID: 26521788 |
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 |
Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy. | Coutinho MC | Circulation. Cardiovascular imaging | 2013 | PMID: 23833285 |
High prevalence of ATTR amyloidosis in endomyocardial biopsy-proven cardiac amyloidosis patients. | Nakagawa M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23638696 |
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 |
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 |
Report of five rare or previously unknown amyloidogenic transthyretin mutations disclosed in Sweden. | Suhr OB | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2009 | PMID: 19922332 |
Biochemical characteristics of variant transthyretins causing hereditary leptomeningeal amyloidosis. | Mitsuhashi S | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2005 | PMID: 16399646 |
Familial amyloid polyneuropathy related to transthyretin mutation Val30 to Leu in a Japanese family. | Utsugisawa K | Muscle & nerve | 1998 | PMID: 9843084 |
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 |
A novel transthyretin mutation at position 30 (Leu for Val) associated with familial amyloidotic polyneuropathy. | Murakami T | Biochemical and biophysical research communications | 1992 | PMID: 1520326 |
click to load more click to collapse |
Text-mined citations for rs28933979 ...
HelpRecord last updated Apr 15, 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.