ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.200G>A (p.Gly67Glu)
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.200G>A (p.Gly67Glu)
Variation ID: 803481 Accession: VCV000803481.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31593026 (GRCh38) [ NCBI UCSC ] 18: 29172989 (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 Jan 11, 2020 Feb 14, 2024 Sep 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.200G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Gly67Glu missense NC_000018.10:g.31593026G>A NC_000018.9:g.29172989G>A NG_009490.1:g.6260G>A LRG_416:g.6260G>A LRG_416t1:c.200G>A - Protein change
- G67E
- Other names
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- Canonical SPDI
- NC_000018.10:31593025: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2022 | RCV000990082.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2014 | RCV002416270.1 |
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
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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
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140870.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Pathogenic
(Sep 24, 2014)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002722872.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.G67E pathogenic mutation (also known as c.200G>A and G47E), located in coding exon 2 of the TTR gene, results from a G to A … (more)
The p.G67E pathogenic mutation (also known as c.200G>A and G47E), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 200. The amino acid change results in glycine to glutamic acid at codon 67. This change occurs in the last base pair of exon 2 which makes it likely to have some effect on normal mRNA splicing; however, direct evidence is not available. Two disease-causing mutations, p.G67A and p.G67R, have been described in the same codon. This pathogenic mutation was first identified in two siblings presenting in their late third decade with peripheral neuropathy, autonomic dysfunction and a family history consistent with familial amyloid polyneuropathy; there was rapid progression of disease in this family along with anticipation in the age of onset of symptoms (Pelo E et al. Amyloid. 2002;9(1):35-41). A functional study found this mutation lead to decreased conformational stability (Altland K et al. Electrophoresis. 2007;28(12):2053-64). An additional study identified this mutation in two unrelated individuals presenting with predominantly neurologic symptoms in their fourth decade; both patients had symptoms of renal impairment, motoric, sensoric, and autonomic polyneuropathy and one patient additionally had restrictive cardiac function (Barreiros AP et al. Liver Transpl. 2010;16(3):314-23). Based on the supporting evidence, p.G67E is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 22, 2022)
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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: SCV001219052.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.200G nucleotide in the TTR gene. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.200G nucleotide in the TTR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 26986100; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 803481). This variant is also known as p.Gly47Glu. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 12000196, 20209591; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 67 of the TTR protein (p.Gly67Glu). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. (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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Endoscopic Findings of Small-Bowel Lesions in Familial Amyloid Polyneuropathy: A Case Report. | Asakura K | Medicine | 2016 | PMID: 26986100 |
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 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs121918090 ...
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.