VCV000887158.21 - ClinVar

NM_001018005.2(TPM1):c.840T>C (p.Asp280=)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001018005.2(TPM1):c.840T>C (p.Asp280=)

Variation ID: 887158 Accession: VCV000887158.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63064131 (GRCh38) [ NCBI UCSC ] 15: 63356330 (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	May 31, 2020	Oct 8, 2024	May 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.840T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Asp280=	synonymous
NM_000366.6:c.840T>C	NP_000357.3:p.Asp280=	synonymous
NM_001018004.2:c.772+1486T>C		intron variant
NM_001018006.2:c.772+1486T>C		intron variant
NM_001018007.2:c.772+1486T>C		intron variant
NM_001018008.2:c.664+1486T>C		intron variant
NM_001018020.2:c.772+1486T>C		intron variant
NM_001301244.2:c.840T>C	NP_001288173.1:p.Asp280=	synonymous
NM_001301289.2:c.664+1486T>C		intron variant
NM_001330344.2:c.664+1486T>C		intron variant
NM_001330346.2:c.732T>C	NP_001317275.1:p.Asp244=	synonymous
NM_001330351.2:c.664+1486T>C		intron variant
NM_001365776.1:c.772+1486T>C		intron variant
NM_001365777.1:c.772+1486T>C		intron variant
NM_001365778.1:c.898+1486T>C		intron variant
NM_001365779.1:c.840T>C	NP_001352708.1:p.Asp280=	synonymous
NM_001365780.1:c.664+1486T>C		intron variant
NM_001365781.2:c.732T>C	NP_001352710.1:p.Asp244=	synonymous
NM_001365782.1:c.732T>C	NP_001352711.1:p.Asp244=	synonymous
NC_000015.10:g.63064131T>C
NC_000015.9:g.63356330T>C
NG_007557.1:g.26493T>C
LRG_387:g.26493T>C
LRG_387t1:c.840T>C	LRG_387p1:p.Asp280=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000015.10:63064130:T:C

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) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs749271066 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	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.
Hypertrophic cardiomyopathy 3	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001119718.4
Dilated cardiomyopathy 1Y	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001119719.4
Cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Dec 31, 2018	RCV001192109.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 6, 2024	RCV002445390.3
TPM1-related disorder	Likely benign (1)	no assertion criteria provided	Mar 26, 2019	RCV003963064.2
Hypertrophic cardiomyopathy	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001495214.9
not provided	Likely benign (1)	criteria provided, single submitter	May 13, 2021	RCV001593282.3

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 (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypertrophic cardiomyopathy 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278149.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1Y Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278150.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Dec 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001360085.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Likely benign (May 13, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001814387.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Likely benign (Jan 15, 2024)	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: SCV001699885.4 First in ClinVar: Jun 08, 2021 Last updated: Feb 14, 2024
Likely Benign (Feb 05, 2024)	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: SCV004815471.1 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)	Number of individuals with the variant: 6
Uncertain significance (May 06, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002679380.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Comment: The c.840T>C variant (also known as p.D280D), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide … (more) The c.840T>C variant (also known as p.D280D), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 840. This nucleotide substitution does not change the aspartic acid at codon 280. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Likely benign (Mar 26, 2019)	no assertion criteria provided Method: clinical testing	TPM1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004790166.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The c.840T>C variant (also known as p.D280D), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 840. This nucleotide substitution does not change the aspartic acid at codon 280. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs749271066 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001018005.2(TPM1):c.840T>C (p.Asp280=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs749271066 ...