ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.188C>T (p.Ala63Val)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.188C>T (p.Ala63Val)
Variation ID: 31877 Accession: VCV000031877.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63044100 (GRCh38) [ NCBI UCSC ] 15: 63336299 (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 Apr 4, 2013 May 1, 2024 Jun 23, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.188C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Ala63Val missense NM_000366.6:c.188C>T NP_000357.3:p.Ala63Val missense NM_001018004.2:c.188C>T NP_001018004.1:p.Ala63Val missense NM_001018006.2:c.188C>T NP_001018006.1:p.Ala63Val missense NM_001018007.2:c.240+269C>T intron variant NM_001018020.2:c.240+269C>T intron variant NM_001301244.2:c.240+269C>T intron variant NM_001365776.1:c.188C>T NP_001352705.1:p.Ala63Val missense NM_001365777.1:c.188C>T NP_001352706.1:p.Ala63Val missense NM_001365778.1:c.314C>T NP_001352707.1:p.Ala105Val missense NM_001365779.1:c.188C>T NP_001352708.1:p.Ala63Val missense NC_000015.10:g.63044100C>T NC_000015.9:g.63336299C>T NG_007557.1:g.6462C>T LRG_387:g.6462C>T LRG_387t1:c.188C>T LRG_387p1:p.Ala63Val P09493:p.Ala63Val - Protein change
- A63V, A105V
- Other names
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- Canonical SPDI
- NC_000015.10:63044099:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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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TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
840 | 889 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000024573.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 23, 2022 | RCV000229431.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 9, 2021 | RCV000619544.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV002470718.1 |
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
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. |
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Pathogenic
(Jun 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000285666.6
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 12006676, 12900417, 15059934, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 12006676, 12900417, 15059934, 15479242, 20161772). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 31877). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 8774330, 30022097; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 63 of the TPM1 protein (p.Ala63Val). (less)
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Uncertain significance
(Aug 09, 2021)
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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: SCV000740245.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.188C>T (p.A63V) alteration is located in exon 2 (coding exon 2) of the TPM1 gene. This alteration results from a C to T substitution … (more)
The c.188C>T (p.A63V) alteration is located in exon 2 (coding exon 2) of the TPM1 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the alanine (A) at amino acid position 63 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Jan 12, 2018)
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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: SCV000589543.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment:
The A63V likely pathogenic variant in the TPM1 gene has been reported in multiple individuals with HCM (Nakajima-Taniguchi et al., 1995; Yamauchi-Takihara et al., 1996; … (more)
The A63V likely pathogenic variant in the TPM1 gene has been reported in multiple individuals with HCM (Nakajima-Taniguchi et al., 1995; Yamauchi-Takihara et al., 1996; Lopes et al., 2015). Additionally, A63V is classified as a likely pathogenic variant by another clinical laboratory in ClinVar (SCV000285666.2; Landrum et al., 2016). The A63V variant is not observed in large population cohorts (Lek et al., 2016). Although the A63V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, functional studies show that the A63V variant destabilizes the tropomyosin protein and results in muscle cell dysfunction (Michele et al., 2002; Heller et al., 2003; Hilario et al., 2004). (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766862.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes, p.(Ala63Pro) and p.(Ala63Thr), have been reported as VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS, but more commonly as likely pathogenic, and observed in at least eleven unrelated individuals with hypertrophic cardiomyopathy (HCM) (ClinVar, PMID: 24170035, PMID: 8523464, PMID: 8774330, PMID: 29398688, PMID: 30022097, PMID: 25351510). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated within a family with HCM (PMID: 24170035), but also observed in several unaffected relatives (personal communication). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been proven to result in reduced effectiveness in regulating ATPase activity and heat instability (PMID: 15479242). Additionally, when transfected into rat cardiac myocytes this variant resulted in slowed cell relengthening (PMID: 15059934). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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not provided
(Apr 15, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045879.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045879.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1. | Moraczewska J | Journal of muscle research and cell motility | 2020 | PMID: 31270709 |
Coverage and diagnostic yield of Whole Exome Sequencing for the Evaluation of Cases with Dilated and Hypertrophic Cardiomyopathy. | Mak TSH | Scientific reports | 2018 | PMID: 30022097 |
Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing. | Teramoto R | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 29398688 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Primary prevention of sudden cardiac death in a low-risk child with familial hypertrophic cardiomyopathy: the role of cardiac magnetic resonance imaging. | Yamazawa H | Clinical research in cardiology : official journal of the German Cardiac Society | 2014 | PMID: 24170035 |
Combinatorial effects of double cardiomyopathy mutant alleles in rodent myocytes: a predictive cellular model of myofilament dysregulation in disease. | Davis J | PloS one | 2010 | PMID: 20161772 |
Effects of cardiomyopathic mutations on the biochemical and biophysical properties of the human alpha-tropomyosin. | Hilario E | European journal of biochemistry | 2004 | PMID: 15479242 |
Parvalbumin corrects slowed relaxation in adult cardiac myocytes expressing hypertrophic cardiomyopathy-linked alpha-tropomyosin mutations. | Coutu P | Circulation research | 2004 | PMID: 15059934 |
Cardiomyopathic tropomyosin mutations that increase thin filament Ca2+ sensitivity and tropomyosin N-domain flexibility. | Heller MJ | The Journal of biological chemistry | 2003 | PMID: 12900417 |
Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins. | Michele DE | Physiological genomics | 2002 | PMID: 12006676 |
Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. | Yamauchi-Takihara K | Heart (British Cardiac Society) | 1996 | PMID: 8774330 |
Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. | Nakajima-Taniguchi C | Journal of molecular and cellular cardiology | 1995 | PMID: 8523464 |
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Text-mined citations for rs199476306 ...
HelpRecord last updated May 01, 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.