VCV000031889.35 - ClinVar

NM_001018005.2(TPM1):c.486T>C (p.Tyr162=)

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.

(19)

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.

Benign/Likely benign

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.486T>C (p.Tyr162=)

Variation ID: 31889 Accession: VCV000031889.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63059674 (GRCh38) [ NCBI UCSC ] 15: 63351873 (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 29, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.486T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Tyr162=	synonymous
NM_000366.6:c.486T>C	NP_000357.3:p.Tyr162=	synonymous
NM_001018004.2:c.486T>C	NP_001018004.1:p.Tyr162=	synonymous
NM_001018006.2:c.486T>C	NP_001018006.1:p.Tyr162=	synonymous
NM_001018007.2:c.486T>C	NP_001018007.1:p.Tyr162=	synonymous
NM_001018008.2:c.378T>C	NP_001018008.1:p.Tyr126=	synonymous
NM_001018020.2:c.486T>C	NP_001018020.1:p.Tyr162=	synonymous
NM_001301244.2:c.486T>C	NP_001288173.1:p.Tyr162=	synonymous
NM_001301289.2:c.378T>C	NP_001288218.1:p.Tyr126=	synonymous
NM_001330344.2:c.378T>C	NP_001317273.1:p.Tyr126=	synonymous
NM_001330346.2:c.378T>C	NP_001317275.1:p.Tyr126=	synonymous
NM_001330351.2:c.378T>C	NP_001317280.1:p.Tyr126=	synonymous
NM_001365776.1:c.486T>C	NP_001352705.1:p.Tyr162=	synonymous
NM_001365777.1:c.486T>C	NP_001352706.1:p.Tyr162=	synonymous
NM_001365778.1:c.612T>C	NP_001352707.1:p.Tyr204=	synonymous
NM_001365779.1:c.486T>C	NP_001352708.1:p.Tyr162=	synonymous
NM_001365780.1:c.378T>C	NP_001352709.1:p.Tyr126=	synonymous
NM_001365781.2:c.378T>C	NP_001352710.1:p.Tyr126=	synonymous
NM_001365782.1:c.378T>C	NP_001352711.1:p.Tyr126=	synonymous
NC_000015.10:g.63059674T>C
NC_000015.9:g.63351873T>C
NG_007557.1:g.22036T>C
LRG_387:g.22036T>C
LRG_387t1:c.486T>C	LRG_387p1:p.Tyr162=

... more HGVS ... less HGVS

Protein change

Other names

p.Y162Y:TAT>TAC

Canonical SPDI

NC_000015.10:63059673:T:C

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

probably no functional consequence

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.

0.02416 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.02405

1000 Genomes Project 0.02416

Trans-Omics for Precision Medicine (TOPMed) 0.04452

The Genome Aggregation Database (gnomAD) 0.05001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.05090

Exome Aggregation Consortium (ExAC) 0.05331

The Genome Aggregation Database (gnomAD), exomes 0.05413

Links

Leiden Muscular Dystrophy (TPM1): TPM1_00020 dbSNP: rs11558747 ClinGen: CA018083 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.
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Apr 10, 2023	RCV000036337.21
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	-	RCV000024585.9
Dilated cardiomyopathy 1Y	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000338013.5
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Mar 17, 2015	RCV000243351.3
Hypertrophic cardiomyopathy	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000399052.13
Cardiomyopathy	Benign (3)	criteria provided, multiple submitters, no conflicts	Sep 27, 2022	RCV001170567.6
Hypertrophic cardiomyopathy 3	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV001094283.4

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.
Benign (Jun 27, 2011)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169033.11 First in ClinVar: Jun 23, 2014 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (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: SCV000393210.3 First in ClinVar: Dec 06, 2016 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (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: SCV000393209.3 First in ClinVar: Dec 06, 2016 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jul 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333154.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Benign (Mar 17, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000317458.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000305849.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (May 10, 2016)	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: SCV000059989.6 First in ClinVar: May 03, 2013 Last updated: Sep 22, 2018	Publications: PubMed (1) PubMed: 24183960 Comment: p.Tyr162Tyr in exon 4 of TPM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue … (more) p.Tyr162Tyr in exon 4 of TPM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8% (5101/66566) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs11558747). (less) Number of individuals with the variant: 518
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987487.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Benign (Apr 03, 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: SCV001349540.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Benign (Sep 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003803073.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Likely benign (Sep 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic Cardiomyopathy Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003803653.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Benign (Apr 10, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003929101.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023
Benign (Feb 01, 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: SCV000558813.8 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024
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: SCV004815451.1 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: 12403
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005215020.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958374.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924768.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973183.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (Apr 15, 2012)	no classification provided Method: curation	not specified Affected status: not provided Allele origin: germline	Leiden Muscular Dystrophy (TPM1) Accession: SCV000045894.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

p.Tyr162Tyr in exon 4 of TPM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8% (5101/66566) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs11558747).

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.
probably no functional consequence			Leiden Muscular Dystrophy (TPM1) Accession: SCV000045894.1

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
DNA sequence capture and next-generation sequencing for the molecular diagnosis of genetic cardiomyopathies.	D'Argenio V	The Journal of molecular diagnostics : JMD	2014	PMID: 24183960

Text-mined citations for rs11558747 ...

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.486T>C (p.Tyr162=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11558747 ...