VCV000031876.12 - ClinVar

NM_001018005.2(TPM1):c.184G>C (p.Glu62Gln)

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.

Likely pathogenic

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.184G>C (p.Glu62Gln)

Variation ID: 31876 Accession: VCV000031876.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63044096 (GRCh38) [ NCBI UCSC ] 15: 63336295 (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	Aug 11, 2024	Mar 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.184G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Glu62Gln	missense
NM_000366.6:c.184G>C	NP_000357.3:p.Glu62Gln	missense
NM_001018004.2:c.184G>C	NP_001018004.1:p.Glu62Gln	missense
NM_001018006.2:c.184G>C	NP_001018006.1:p.Glu62Gln	missense
NM_001018007.2:c.240+265G>C		intron variant
NM_001018020.2:c.240+265G>C		intron variant
NM_001301244.2:c.240+265G>C		intron variant
NM_001365776.1:c.184G>C	NP_001352705.1:p.Glu62Gln	missense
NM_001365777.1:c.184G>C	NP_001352706.1:p.Glu62Gln	missense
NM_001365778.1:c.310G>C	NP_001352707.1:p.Glu104Gln	missense
NM_001365779.1:c.184G>C	NP_001352708.1:p.Glu62Gln	missense
NC_000015.10:g.63044096G>C
NC_000015.9:g.63336295G>C
NG_007557.1:g.6458G>C
LRG_387:g.6458G>C
LRG_387t1:c.184G>C	LRG_387p1:p.Glu62Gln

... more HGVS ... less HGVS

Protein change

E62Q, E104Q

Other names

Canonical SPDI

NC_000015.10:63044095:G:C

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

functional variant; Sequence Ontology [ SO:0001536]

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.

Links

ClinGen: CA018692 Leiden Muscular Dystrophy (TPM1): TPM1_00004 dbSNP: rs199476305 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 provided	Pathogenic (5)	no assertion criteria provided	-	RCV000024572.9
Hypertrophic cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000768494.2
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Mar 18, 2024	RCV004686570.1

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.
Likely pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Human Genetics, University of Leuven Accession: SCV000886799.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019
Likely pathogenic (Mar 18, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005178971.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (9) PubMed: 12651045‚ 25241052‚ 25520664‚ 25548289‚ 28759816‚ 29626422‚ 31513939‚ 32882290‚ 34194005 Comment: The p.E62Q variant (also known as c.184G>C), located in coding exon 2 of the TPM1 gene, results from a G to C substitution at nucleotide … (more) The p.E62Q variant (also known as c.184G>C), located in coding exon 2 of the TPM1 gene, results from a G to C substitution at nucleotide position 184. The glutamic acid at codon 62 is replaced by glutamine, an amino acid with highly similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI:dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant was reported in multiple individuals with features consistent with hypertrophic (HCM), dilated cardiomyopathy (DCM) or unspecified cardiomyopathy, and segregated with disease in a family with HCM and sudden death (Jongbloed RJ et al. J Am Coll Cardiol, 2003 Mar;41:981-6; Te Rijdt WP et al. Cardiovasc Pathol, 2017 May;30:23-26; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Stroeks SLVM et al. Genet Med, 2021 Nov;23:2186-2193). Functional studies indicate this variant may impact protein function; however, additional evidence is needed to confirm these findings (Chang AN et al. Front Physiol, 2014 Dec;5:460; Dorsch LM et al. Int J Cardiol, 2021 Jan;323:251-258; Farman GP et al. Arch Biochem Biophys, 2018 Jun;647:84-92). This variant is considered to be rare based on population 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 (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739879.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001917189.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001952318.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001970223.1 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: SCV000045878.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013

Comment:

The p.E62Q variant (also known as c.184G>C), located in coding exon 2 of the TPM1 gene, results from a G to C substitution at nucleotide position 184. The glutamic acid at codon 62 is replaced by glutamine, an amino acid with highly similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI:dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant was reported in multiple individuals with features consistent with hypertrophic (HCM), dilated cardiomyopathy (DCM) or unspecified cardiomyopathy, and segregated with disease in a family with HCM and sudden death (Jongbloed RJ et al. J Am Coll Cardiol, 2003 Mar;41:981-6; Te Rijdt WP et al. Cardiovasc Pathol, 2017 May;30:23-26; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Stroeks SLVM et al. Genet Med, 2021 Nov;23:2186-2193). Functional studies indicate this variant may impact protein function; however, additional evidence is needed to confirm these findings (Chang AN et al. Front Physiol, 2014 Dec;5:460; Dorsch LM et al. Int J Cardiol, 2021 Jan;323:251-258; Farman GP et al. Arch Biochem Biophys, 2018 Jun;647:84-92). This variant is considered to be rare based on population 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: SCV000045878.1

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
The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.	Dorsch LM	International journal of cardiology	2021	PMID: 32882290
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
HCM and DCM cardiomyopathy-linked α-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments.	Farman GP	Archives of biochemistry and biophysics	2018	PMID: 29626422
Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy.	Te Rijdt WP	Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology	2017	PMID: 28759816
Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies.	Gupte TM	The Journal of biological chemistry	2015	PMID: 25548289
Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin.	Chang AN	Frontiers in physiology	2014	PMID: 25520664
Energy landscapes reveal the myopathic effects of tropomyosin mutations.	Orzechowski M	Archives of biochemistry and biophysics	2014	PMID: 25241052
Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.	Jongbloed RJ	Journal of the American College of Cardiology	2003	PMID: 12651045

Text-mined citations for rs199476305 ...

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 Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_001018005.2(TPM1):c.184G>C (p.Glu62Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199476305 ...