This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). 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"). ClinVar contains an entry for this variant (Variation ID: 12457). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 11136687, 29540472). It has also been observed to segregate with disease in related individuals.
ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.284T>C (p.Val95Ala)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001018005.2(TPM1):c.284T>C (p.Val95Ala)
Variation ID: 12457 Accession: VCV000012457.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q22.2 15: 63057028 (GRCh38) [ NCBI UCSC ] 15: 63349227 (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 Sep 16, 2024 Jul 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001018005.2:c.284T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Val95Ala missense NM_000366.6:c.284T>C NP_000357.3:p.Val95Ala missense NM_001018004.2:c.284T>C NP_001018004.1:p.Val95Ala missense NM_001018006.2:c.284T>C NP_001018006.1:p.Val95Ala missense NM_001018007.2:c.284T>C NP_001018007.1:p.Val95Ala missense NM_001018008.2:c.176T>C NP_001018008.1:p.Val59Ala missense NM_001018020.2:c.284T>C NP_001018020.1:p.Val95Ala missense NM_001301244.2:c.284T>C NP_001288173.1:p.Val95Ala missense NM_001301289.2:c.176T>C NP_001288218.1:p.Val59Ala missense NM_001330344.2:c.176T>C NP_001317273.1:p.Val59Ala missense NM_001330346.2:c.176T>C NP_001317275.1:p.Val59Ala missense NM_001330351.2:c.176T>C NP_001317280.1:p.Val59Ala missense NM_001365776.1:c.284T>C NP_001352705.1:p.Val95Ala missense NM_001365777.1:c.284T>C NP_001352706.1:p.Val95Ala missense NM_001365778.1:c.410T>C NP_001352707.1:p.Val137Ala missense NM_001365779.1:c.284T>C NP_001352708.1:p.Val95Ala missense NM_001365780.1:c.176T>C NP_001352709.1:p.Val59Ala missense NM_001365781.2:c.176T>C NP_001352710.1:p.Val59Ala missense NM_001365782.1:c.176T>C NP_001352711.1:p.Val59Ala missense NC_000015.10:g.63057028T>C NC_000015.9:g.63349227T>C NG_007557.1:g.19390T>C LRG_387:g.19390T>C LRG_387t1:c.284T>C LRG_387p1:p.Val95Ala - Protein change
- V95A, V137A, V59A
- Other names
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p.V95A:GTT>GCT
- Canonical SPDI
- NC_000015.10:63057027:T:C
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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.
- -
-
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. |
|||
| TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
856 | 904 | |
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) |
no assertion criteria provided
|
Jan 2, 2001 | RCV000013273.27 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2023 | RCV000211870.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 30, 2024 | RCV000159356.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 25, 2020 | RCV000619092.4 |
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
(Jan 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001230836.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). 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"). ClinVar contains an entry for this variant (Variation ID: 12457). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 11136687, 29540472). It has also been observed to segregate with disease in related individuals. (less)
|
|
|
Pathogenic
(Jul 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209302.12
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in increased thin filament Ca2+ sensitivity and alters the rate of myosin cycling (PMID: 11136687); This variant is associated with the following publications: (PMID: 21295541, 21320446, 29540472, 11136687, 32880476, 22187526) (less)
|
|
|
Pathogenic
(Oct 06, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203873.5
First in ClinVar: Jan 31, 2015 Last updated: Jun 01, 2016 |
Comment:
The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 … (more)
The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Sep 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740262.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide … (more)
The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 284. The valine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration was reported to segregate with hypertrophic cardiomyopathy in a multi-generation family with reduced penetrance (Karibe A et al. Circulation, 2001 Jan;103:65-71). This variant has also been detected in a dilated cardiomypathy cohort (Hazebroek MR et al. Circ Heart Fail. 2018 03;11(3):e004682). In vitro assays suggested that this mutant would affect protein structure and function (Karibe A et al. Circulation, 2001 Jan;103:65-71; Bai F et al. Biophys. J., 2011 Feb;100:1014-23; Mathur MC et al. Biochem. Biophys. Res. Commun., 2011 Mar;406:74-8; Wang F et al. J. Biomed. Biotechnol., 2011 Dec;2011:435271). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Pathogenic
(Jan 02, 2001)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033520.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
Karibe et al. (2001) described a large Spanish American family in which multiple members had hypertrophic cardiomyopathy (CMH3; 115196). They found a novel val95-to-ala (V95A) … (more)
Karibe et al. (2001) described a large Spanish American family in which multiple members had hypertrophic cardiomyopathy (CMH3; 115196). They found a novel val95-to-ala (V95A) mutation in TPM1 to segregate with the disease phenotype. This mutation was associated with the same mild degree of left ventricular hypertrophy as seen in some CMH1 families harboring specific mutations in MYH7 (160760.0010, 160760.0012, 160760.0001). Penetrance was estimated at 53% on the basis of an abnormal echocardiogram; however, 2 mutation carriers with normal echocardiograms and normal ECGs were only in their mid-thirties at the time of the study. Penetrance could not be accurately assessed by ECG, since 6 older mutation-negative family members had minor T-wave changes. Cumulative survival rates in this family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years. Expression of mutant and control tropomyosin in a bacterial system allowed a functional assessment of this mutation. An increase in calcium binding and abnormal myosin cycling were observed; both were felt to be important contributors to disease pathogenesis. (less)
|
|
|
not provided
(Apr 15, 2012)
|
no classification provided
Method: curation
|
Familial hypertrophic cardiomyopathy 3
Affected status: not provided
Allele origin:
germline
|
Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045881.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in increased thin filament Ca2+ sensitivity and alters the rate of myosin cycling (PMID: 11136687); This variant is associated with the following publications: (PMID: 21295541, 21320446, 29540472, 11136687, 32880476, 22187526)
Comment:
The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence.
Comment:
The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 284. The valine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration was reported to segregate with hypertrophic cardiomyopathy in a multi-generation family with reduced penetrance (Karibe A et al. Circulation, 2001 Jan;103:65-71). This variant has also been detected in a dilated cardiomypathy cohort (Hazebroek MR et al. Circ Heart Fail. 2018 03;11(3):e004682). In vitro assays suggested that this mutant would affect protein structure and function (Karibe A et al. Circulation, 2001 Jan;103:65-71; Bai F et al. Biophys. J., 2011 Feb;100:1014-23; Mathur MC et al. Biochem. Biophys. Res. Commun., 2011 Mar;406:74-8; Wang F et al. J. Biomed. Biotechnol., 2011 Dec;2011:435271). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
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. |
|---|---|---|---|---|
|
has functional consequence
|
Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045881.1
|
|
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). 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"). ClinVar contains an entry for this variant (Variation ID: 12457). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 11136687, 29540472). It has also been observed to segregate with disease in related individuals.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in increased thin filament Ca2+ sensitivity and alters the rate of myosin cycling (PMID: 11136687); This variant is associated with the following publications: (PMID: 21295541, 21320446, 29540472, 11136687, 32880476, 22187526)
Comment:
The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence.
Comment:
The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 284. The valine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration was reported to segregate with hypertrophic cardiomyopathy in a multi-generation family with reduced penetrance (Karibe A et al. Circulation, 2001 Jan;103:65-71). This variant has also been detected in a dilated cardiomypathy cohort (Hazebroek MR et al. Circ Heart Fail. 2018 03;11(3):e004682). In vitro assays suggested that this mutant would affect protein structure and function (Karibe A et al. Circulation, 2001 Jan;103:65-71; Bai F et al. Biophys. J., 2011 Feb;100:1014-23; Mathur MC et al. Biochem. Biophys. Res. Commun., 2011 Mar;406:74-8; Wang F et al. J. Biomed. Biotechnol., 2011 Dec;2011:435271). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy. | Hazebroek MR | Circulation. Heart failure | 2018 | PMID: 29540472 |
| Functional effects of substitutions I92T and V95A in actin-binding period 3 of tropomyosin. | Śliwinska M | Biochimica et biophysica acta. Proteins and proteomics | 2018 | PMID: 29496559 |
| Facilitated cross-bridge interactions with thin filaments by familial hypertrophic cardiomyopathy mutations in α-tropomyosin. | Wang F | Journal of biomedicine & biotechnology | 2011 | PMID: 22187526 |
| Enhanced active cross-bridges during diastole: molecular pathogenesis of tropomyosin's HCM mutations. | Bai F | Biophysical journal | 2011 | PMID: 21320446 |
| Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin. | Mathur MC | Biochemical and biophysical research communications | 2011 | PMID: 21295541 |
| Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. | Karibe A | Circulation | 2001 | PMID: 11136687 |
Text-mined citations for rs104894504 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.