VCV000043442.16 - ClinVar

NM_001018005.2(TPM1):c.829G>A (p.Ala277Thr)

Germline

Classification

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.

(7)

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.

Uncertain significance

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.829G>A (p.Ala277Thr)

Variation ID: 43442 Accession: VCV000043442.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63064120 (GRCh38) [ NCBI UCSC ] 15: 63356319 (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	Jan 31, 2015	Jul 23, 2024	Jun 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.829G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Ala277Thr	missense
NM_000366.6:c.829G>A	NP_000357.3:p.Ala277Thr	missense
NM_001018004.2:c.772+1475G>A		intron variant
NM_001018006.2:c.772+1475G>A		intron variant
NM_001018007.2:c.772+1475G>A		intron variant
NM_001018008.2:c.664+1475G>A		intron variant
NM_001018020.2:c.772+1475G>A		intron variant
NM_001301244.2:c.829G>A	NP_001288173.1:p.Ala277Thr	missense
NM_001301289.2:c.664+1475G>A		intron variant
NM_001330344.2:c.664+1475G>A		intron variant
NM_001330346.2:c.721G>A	NP_001317275.1:p.Ala241Thr	missense
NM_001330351.2:c.664+1475G>A		intron variant
NM_001365776.1:c.772+1475G>A		intron variant
NM_001365777.1:c.772+1475G>A		intron variant
NM_001365778.1:c.898+1475G>A		intron variant
NM_001365779.1:c.829G>A	NP_001352708.1:p.Ala277Thr	missense
NM_001365780.1:c.664+1475G>A		intron variant
NM_001365781.2:c.721G>A	NP_001352710.1:p.Ala241Thr	missense
NM_001365782.1:c.721G>A	NP_001352711.1:p.Ala241Thr	missense
NC_000015.10:g.63064120G>A
NC_000015.9:g.63356319G>A
NG_007557.1:g.26482G>A
LRG_387:g.26482G>A
LRG_387t1:c.829G>A	LRG_387p1:p.Ala277Thr

... more HGVS ... less HGVS

Protein change

A277T, A241T

Other names

Canonical SPDI

NC_000015.10:63064119:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00011

Links

ClinGen: CA018371 dbSNP: rs149659674 VarSome

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
Gene	OMIM	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	854	902

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2012	RCV000036362.5
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 28, 2023	RCV001192355.4
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 23, 2023	RCV001852756.7
Dilated cardiomyopathy 1Y Hypertrophic cardiomyopathy 3	Uncertain significance (1)	criteria provided, single submitter	Sep 3, 2021	RCV002496557.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 26, 2023	RCV003343609.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 28, 2024	RCV004589528.1

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.
Uncertain significance (Oct 31, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060014.6 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Comment: Variant classified as Uncertain Significance - Favor Benign. The Ala277Thr varia nt in TPM1 has not been reported in the literature. This variant has been … (more) Variant classified as Uncertain Significance - Favor Benign. The Ala277Thr varia nt in TPM1 has not been reported in the literature. This variant has been identi fied in 2 Black individuals with HCM tested by our laboratory (including this in dividual) and has been identified in 1/4406 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS; dbSNP rs149659674). Alanine (Ala) at position 277 is not well conserve d in evolution with several species carrying the mutant amino acid (threonine). This suggests that this variant is tolerated but is insufficient to rule out a role in disease. Additional information is needed to fully assess the clinical s ignificance of the Ala277Thr variant. (less) Number of individuals with the variant: 2
Uncertain significance (Aug 26, 2023)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004074915.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Publications: PubMed (2) PubMed: 25611685‚ 34194005 Comment: The p.A277T variant (also known as c.829G>A), located in coding exon 9 of the TPM1 gene, results from a G to A substitution at nucleotide … (more) The p.A277T variant (also known as c.829G>A), located in coding exon 9 of the TPM1 gene, results from a G to A substitution at nucleotide position 829. The alanine at codon 277 is replaced by threonine, an amino acid with similar properties. This variant has been reported in hypertrophic and dilated cardiomyopathy cohorts, but clinical details were limited (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Stroeks SLVM et al. Genet Med, 2021 Nov;23:2186-2193). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Sep 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001360403.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27532257‚ 32880476 Comment: This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257) and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 8/282436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002156020.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 32880476 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 277 of the TPM1 protein (p.Ala277Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 277 of the TPM1 protein (p.Ala277Thr). This variant is present in population databases (rs149659674, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 43442). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004815468.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 27532257‚ 32880476 Comment: This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257) and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 8/282436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 6
Uncertain significance (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 3 Dilated cardiomyopathy 1Y Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002794517.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jun 28, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005078448.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34699384, 34194005, 32880476)

Comment:

Variant classified as Uncertain Significance - Favor Benign. The Ala277Thr varia nt in TPM1 has not been reported in the literature. This variant has been identi fied in 2 Black individuals with HCM tested by our laboratory (including this in dividual) and has been identified in 1/4406 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS; dbSNP rs149659674). Alanine (Ala) at position 277 is not well conserve d in evolution with several species carrying the mutant amino acid (threonine). This suggests that this variant is tolerated but is insufficient to rule out a role in disease. Additional information is needed to fully assess the clinical s ignificance of the Ala277Thr variant.

Comment:

The p.A277T variant (also known as c.829G>A), located in coding exon 9 of the TPM1 gene, results from a G to A substitution at nucleotide position 829. The alanine at codon 277 is replaced by threonine, an amino acid with similar properties. This variant has been reported in hypertrophic and dilated cardiomyopathy cohorts, but clinical details were limited (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Stroeks SLVM et al. Genet Med, 2021 Nov;23:2186-2193). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257) and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 8/282436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 277 of the TPM1 protein (p.Ala277Thr). This variant is present in population databases (rs149659674, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 43442). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy.	Stroeks SLVM	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34194005
Implications of Genetic Testing in Dilated Cardiomyopathy.	Verdonschot JAJ	Circulation. Genomic and precision medicine	2020	PMID: 32880476
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685

Text-mined citations for rs149659674 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_001018005.2(TPM1):c.829G>A (p.Ala277Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149659674 ...