ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.194C>A (p.Ala65Asp)
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.194C>A (p.Ala65Asp)
Variation ID: 181702 Accession: VCV000181702.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31593020 (GRCh38) [ NCBI UCSC ] 18: 29172983 (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 Feb 24, 2015 Feb 14, 2024 Aug 1, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.194C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ala65Asp missense NC_000018.10:g.31593020C>A NC_000018.9:g.29172983C>A NG_009490.1:g.6254C>A LRG_416:g.6254C>A LRG_416t1:c.194C>A LRG_416p1:p.Ala65Asp P02766:p.Ala65Asp - Protein change
- A65D
- Other names
- p.A65D:GCC>GAC
- Canonical SPDI
- NC_000018.10:31593019:C: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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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 | 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
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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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May 30, 2017 | RCV000159436.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2019 | RCV001228889.6 |
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
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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
(Jan 19, 2012)
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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: SCV000209382.10
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
This mutation is denoted Ala65Asp (aka A65D) at the protein level and c.194 C>A at the cDNA level. A heterozygous C>A nucleotide substitution in exon … (more)
This mutation is denoted Ala65Asp (aka A65D) at the protein level and c.194 C>A at the cDNA level. A heterozygous C>A nucleotide substitution in exon 2 of the TTR gene results in the replacement of an Alanine codon (GCC) with an Aspartic acid codon (GAC) at amino acid position 65 in transthyretin. The Ala65Asp (aka Ala45Asp, using alternative nomenclature) mutation in the TTR gene has been reported previously in association with cardiac amyloidosis (Saraiva M et al., 1995). The Ala65Asp mutation results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Aspartic acid residue. Additionally, the NHLBI ESP Exome Variant Server reports Ala65Asp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Furthermore, mutations in this codon (Ala65Ser, Ala65Thr) and in nearby codons (Phe64Leu, Phe64Ser, Phe64Tyr, Gly67Ala) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant is found in HCM panel(s). (less)
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Pathogenic
(May 30, 2017)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450358.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 01, 2019)
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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: SCV001401315.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 23713495, 24953234). This variant is also known as A45D … (more)
This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 23713495, 24953234). This variant is also known as A45D in the literature. ClinVar contains an entry for this variant (Variation ID: 181702). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 65 of the TTR protein (p.Ala65Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. 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"). 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.Ala65 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 28460244, 1570831, 10842718), which suggests that this may be a clinically significant amino acid residue. (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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Late onset cardiomyopathy as presenting sign of ATTR A45G amyloidosis caused by a novel TTR mutation (p.A65G). | Klaassen SHC | Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology | 2017 | PMID: 28460244 |
Myopathic phenotype of familial amyloid polyneuropathy with a rare transthyretin variant: ATTR Ala45Asp. | Misumi Y | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 24953234 |
Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. | Ihse E | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23713495 |
Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser. | Janunger T | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2000 | PMID: 10842718 |
Transthyretin mutations in health and disease. | Saraiva MJ | Human mutation | 1995 | PMID: 7599630 |
A new transthyretin mutation associated with amyloid cardiomyopathy. | Saraiva MJ | American journal of human genetics | 1992 | PMID: 1570831 |
Text-mined citations for rs730881169 ...
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.