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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 15, 2023
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:
RCV000622165.5

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:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000740009Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 15, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy.

Watkins H, Anan R, Coviello DA, Spirito P, Seidman JG, Seidman CE.

Circulation. 1995 May 1;91(9):2302-5.

PubMed [citation]
PMID:
7729014

A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity.

Bottinelli R, Coviello DA, Redwood CS, Pellegrino MA, Maron BJ, Spirito P, Watkins H, Reggiani C.

Circ Res. 1998 Jan 9-23;82(1):106-15.

PubMed [citation]
PMID:
9440709
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000740009.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The c.523G>A (p.D175N) alteration is located in exon 5 (coding exon 5) of the TPM1 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/282804) total alleles studied. The highest observed frequency was 0.016% (4/25076) of European (Finnish) alleles. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM). It was initially described in a cohort of Finnish families with HCM with evidence that it stemmed from a common ancestor, although a case of probable de novo occurrence was reported (Watkins, 1995; Jääskeläinen, 2004; Hedman, 2004; Jääskeläinen, 2013). This amino acid position is well conserved in available vertebrate species. Functional studies have shown the presence of this alteration affected local stability of the tropomyosin 1 protein and increased calcium sensitivity and residual ATPase activity, with impact on calcium-dependent signaling cascades (Bottinelli, 1998; Ly, 2012; Robinson, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Jun 23, 2024