ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.200G>T (p.Gly67Val)
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.200G>T (p.Gly67Val)
Variation ID: 938206 Accession: VCV000938206.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q12.1 18: 29172989 (GRCh37) [ NCBI UCSC ] 18: 31593026 (GRCh38) [ 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 Jul 16, 2020 Apr 15, 2024 Feb 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000371.4:c.200G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Gly67Val missense NC_000018.10:g.31593026G>T NC_000018.9:g.29172989G>T NG_009490.1:g.6260G>T LRG_416:g.6260G>T LRG_416t1:c.200G>T - Protein change
- G67V
- Other names
- -
- Canonical SPDI
- NC_000018.10:31593025:G:T
-
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.
-
- Links
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 13, 2024 | RCV001207386.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 3, 2019 | RCV002418694.1 |
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
(Apr 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002722875.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.200G>T pathogenic mutation (also known as p.G67V), located in coding exon 2 of the TTR gene, results from a G to T substitution at … (more)
The c.200G>T pathogenic mutation (also known as p.G67V), located in coding exon 2 of the TTR gene, results from a G to T substitution at nucleotide position 200. The amino acid change results in glycine to valine at codon 67, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in multiple individuals with TTR-related amyloidosis (Saraiva MJ. Hum. Mutat., 1995;5:191-6; Suenaga G et al. Sci Rep, 2017 05;7:1579). Different alterations at this same position (c.200G>C G67A, c.200G>A G67E) have been reported in multiple individuals with TTR-related amyloidosis (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Pelo E et al. Amyloid, 2002 Mar;9:35-41; Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Jun 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001378733.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly67 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20209591, 12000196). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 25997029, 26986100). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 67 of the TTR protein (p.Gly67Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 2 of the TTR coding sequence, which is part of the consensus splice site for this exon. (less)
|
|
Pathogenic
(Feb 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813562.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: TTR c.200G>T (p.Gly67Val) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Five … (more)
Variant summary: TTR c.200G>T (p.Gly67Val) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251460 control chromosomes (gnomAD). c.200G>T has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (Gillmore_2015, Gillmore_2016, Low_2021). These data indicate that the variant is very likely to be associated with disease. 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: 26243339, 27143678, 34059423). ClinVar contains an entry for this variant (Variation ID: 938206). Based on the evidence outlined above, the variant was classified as pathogenic. (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 |
---|---|---|---|---|
Hereditary transthyretin amyloidosis in multi-ethnic Malaysians. | Low SC | Neuromuscular disorders : NMD | 2021 | PMID: 34059423 |
Inflammatory state exists in familial amyloid polyneuropathy that may be triggered by mutated transthyretin. | Suenaga G | Scientific reports | 2017 | PMID: 28484271 |
Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. | Gillmore JD | Circulation | 2016 | PMID: 27143678 |
Endoscopic Findings of Small-Bowel Lesions in Familial Amyloid Polyneuropathy: A Case Report. | Asakura K | Medicine | 2016 | PMID: 26986100 |
A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. | Carr AS | Journal of neurology, neurosurgery, and psychiatry | 2016 | PMID: 26243339 |
Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. | Fontana M | Radiology | 2015 | PMID: 25997029 |
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 |
Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. | Barreiros AP | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2010 | PMID: 20209591 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred. | Pelo E | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2002 | PMID: 12000196 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Transthyretin mutations in health and disease. | Saraiva MJ | Human mutation | 1995 | PMID: 7599630 |
A new mutation (TTR Ala-47) in the transthyretin gene associated with hereditary amyloidosis. | Ferlini A | Human mutation | 1994 | PMID: 7951260 |
click to load more click to collapse |
Text-mined citations for rs121918090 ...
HelpRecord last updated Apr 20, 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.