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NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn) AND Cardiomyopathy

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Oct 4, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001170568.9

Allele description [Variation Report for NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)]

NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)

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.523G>A (p.Asp175Asn)
Other names:
p.D175N:GAC>AAC
HGVS:
  • NC_000015.10:g.63060899G>A
  • NG_007557.1:g.23261G>A
  • NM_000366.6:c.523G>A
  • NM_001018004.2:c.523G>A
  • NM_001018005.2:c.523G>AMANE SELECT
  • NM_001018006.2:c.523G>A
  • NM_001018007.2:c.523G>A
  • NM_001018008.2:c.415G>A
  • NM_001018020.2:c.523G>A
  • NM_001301244.2:c.523G>A
  • NM_001301289.2:c.415G>A
  • NM_001330344.2:c.415G>A
  • NM_001330346.2:c.415G>A
  • NM_001330351.2:c.415G>A
  • NM_001365776.1:c.523G>A
  • NM_001365777.1:c.523G>A
  • NM_001365778.1:c.649G>A
  • NM_001365779.1:c.523G>A
  • NM_001365780.1:c.415G>A
  • NM_001365781.2:c.415G>A
  • NM_001365782.1:c.415G>A
  • NP_000357.3:p.Asp175Asn
  • NP_001018004.1:p.Asp175Asn
  • NP_001018005.1:p.Asp175Asn
  • NP_001018006.1:p.Asp175Asn
  • NP_001018007.1:p.Asp175Asn
  • NP_001018008.1:p.Asp139Asn
  • NP_001018020.1:p.Asp175Asn
  • NP_001288173.1:p.Asp175Asn
  • NP_001288218.1:p.Asp139Asn
  • NP_001317273.1:p.Asp139Asn
  • NP_001317275.1:p.Asp139Asn
  • NP_001317280.1:p.Asp139Asn
  • NP_001352705.1:p.Asp175Asn
  • NP_001352706.1:p.Asp175Asn
  • NP_001352707.1:p.Asp217Asn
  • NP_001352708.1:p.Asp175Asn
  • NP_001352709.1:p.Asp139Asn
  • NP_001352710.1:p.Asp139Asn
  • NP_001352711.1:p.Asp139Asn
  • LRG_387t1:c.523G>A
  • LRG_387:g.23261G>A
  • LRG_387p1:p.Asp175Asn
  • NC_000015.9:g.63353098G>A
  • NM_000366.5:c.523G>A
  • NM_001018005.1:c.523G>A
  • NM_001018006.1:c.523G>A
  • P09493:p.Asp175Asn
  • c.523G>A
  • p.(Asp175Asn)
Protein change:
D139N; ASP175ASN
Links:
Leiden Muscular Dystrophy (TPM1): TPM1_00009; UniProtKB: P09493#VAR_007601; OMIM: 191010.0002; dbSNP: rs104894503
NCBI 1000 Genomes Browser:
rs104894503
Molecular consequence:
  • NM_000366.6:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018004.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018005.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018006.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018007.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018008.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001018020.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001301244.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001301289.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330344.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330346.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330351.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365776.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365777.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365778.1:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365779.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365780.1:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365781.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365782.1:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536]

Condition(s)

Name:
Cardiomyopathy (CMYO)
Synonyms:
Cardiomyopathies
Identifiers:
MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001333156CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 4, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001346437Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 10, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV001333156.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001346437.2

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

Description

This missense variant replaces aspartic acid with asparagine at codon 175 of the TPM1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant increases calcium sensitivity, sliding velocity and the bending flexibility of the thin filaments (PMID: 9245729, 10900175, 22789852, 22794249, 29361520, 30923661). Transgenic mouse expressing this variant only in heart exhibited myocardial functional impairment and histologic structural changes as in the human form of the disease (PMID: 10400910). This variant is a common founder mutation in Finnish population and has been reported in many individuals affected with hypertrophic cardiomyopathy (PMID: 7729014, 8205619, 8523464, 9060904, 14734051, 15000344, 16014439, 16504640, 22239901, 22462493). It has been shown that this variant segregates with the disease in at least three families (PMID: 7729014, 8205619, 9060904). This variant has been identified in 5/282804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

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

Last Updated: Jun 23, 2024