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NM_001018005.2(TPM1):c.539A>T (p.Glu180Val) AND Hypertrophic cardiomyopathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 28, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002513229.2

Allele description [Variation Report for NM_001018005.2(TPM1):c.539A>T (p.Glu180Val)]

NM_001018005.2(TPM1):c.539A>T (p.Glu180Val)

Gene:
TPM1:tropomyosin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q22.2
Genomic location:
Preferred name:
NM_001018005.2(TPM1):c.539A>T (p.Glu180Val)
HGVS:
  • NC_000015.10:g.63060915A>T
  • NG_007557.1:g.23277A>T
  • NM_000366.6:c.539A>T
  • NM_001018004.2:c.539A>T
  • NM_001018005.2:c.539A>TMANE SELECT
  • NM_001018006.2:c.539A>T
  • NM_001018007.2:c.539A>T
  • NM_001018008.2:c.431A>T
  • NM_001018020.2:c.539A>T
  • NM_001301244.2:c.539A>T
  • NM_001301289.2:c.431A>T
  • NM_001330344.2:c.431A>T
  • NM_001330346.2:c.431A>T
  • NM_001330351.2:c.431A>T
  • NM_001365776.1:c.539A>T
  • NM_001365777.1:c.539A>T
  • NM_001365778.1:c.665A>T
  • NM_001365779.1:c.539A>T
  • NM_001365780.1:c.431A>T
  • NM_001365781.2:c.431A>T
  • NM_001365782.1:c.431A>T
  • NP_000357.3:p.Glu180Val
  • NP_001018004.1:p.Glu180Val
  • NP_001018005.1:p.Glu180Val
  • NP_001018006.1:p.Glu180Val
  • NP_001018007.1:p.Glu180Val
  • NP_001018008.1:p.Glu144Val
  • NP_001018020.1:p.Glu180Val
  • NP_001288173.1:p.Glu180Val
  • NP_001288218.1:p.Glu144Val
  • NP_001317273.1:p.Glu144Val
  • NP_001317275.1:p.Glu144Val
  • NP_001317280.1:p.Glu144Val
  • NP_001352705.1:p.Glu180Val
  • NP_001352706.1:p.Glu180Val
  • NP_001352707.1:p.Glu222Val
  • NP_001352708.1:p.Glu180Val
  • NP_001352709.1:p.Glu144Val
  • NP_001352710.1:p.Glu144Val
  • NP_001352711.1:p.Glu144Val
  • LRG_387t1:c.539A>T
  • LRG_387:g.23277A>T
  • LRG_387p1:p.Glu180Val
  • NC_000015.9:g.63353114A>T
  • NM_001018005.1:c.539A>T
  • P09493:p.Glu180Val
  • p.(Gu180Val)
Protein change:
E144V
Links:
Leiden Muscular Dystrophy (TPM1): TPM1_00011; UniProtKB: P09493#VAR_029452; dbSNP: rs104894502
NCBI 1000 Genomes Browser:
rs104894502
Molecular consequence:
  • NM_000366.6:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018004.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018005.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018006.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018007.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018008.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018020.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001301244.2:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001301289.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330344.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330346.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330351.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365776.1:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365777.1:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365778.1:c.665A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365779.1:c.539A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365780.1:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365781.2:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365782.1:c.431A>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536]

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003442952Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 28, 2022) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.

Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE.

Cell. 1994 Jun 3;77(5):701-12.

PubMed [citation]
PMID:
8205619

Effects of two hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on Ca2+ regulation of thin filament motility.

Bing W, Redwood CS, Purcell IF, Esposito G, Watkins H, Marston SB.

Biochem Biophys Res Commun. 1997 Jul 30;236(3):760-4.

PubMed [citation]
PMID:
9245729
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV003442952.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu180 amino acid residue in TPM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8205619, 9245729, 11603924, 22155441, 22789852; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM1 function (PMID: 27983818). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 31880). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11044437; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 180 of the TPM1 protein (p.Glu180Val).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024