NM_001018005.2(TPM1):c.725C>T (p.Ala242Val) AND Primary dilated cardiomyopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV003319174.2

Allele description [Variation Report for NM_001018005.2(TPM1):c.725C>T (p.Ala242Val)]

NM_001018005.2(TPM1):c.725C>T (p.Ala242Val)

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.725C>T (p.Ala242Val)

HGVS:

NC_000015.10:g.63062598C>T
NG_007557.1:g.24960C>T
NM_000366.6:c.725C>T
NM_001018004.2:c.725C>T
NM_001018005.2:c.725C>TMANE SELECT
NM_001018006.2:c.725C>T
NM_001018007.2:c.725C>T
NM_001018008.2:c.617C>T
NM_001018020.2:c.725C>T
NM_001301244.2:c.725C>T
NM_001301289.2:c.617C>T
NM_001330344.2:c.617C>T
NM_001330346.2:c.617C>T
NM_001330351.2:c.617C>T
NM_001365776.1:c.725C>T
NM_001365777.1:c.725C>T
NM_001365778.1:c.851C>T
NM_001365779.1:c.725C>T
NM_001365780.1:c.617C>T
NM_001365781.2:c.617C>T
NM_001365782.1:c.617C>T
NP_000357.3:p.Ala242Val
NP_001018004.1:p.Ala242Val
NP_001018005.1:p.Ala242Val
NP_001018006.1:p.Ala242Val
NP_001018007.1:p.Ala242Val
NP_001018008.1:p.Ala206Val
NP_001018020.1:p.Ala242Val
NP_001288173.1:p.Ala242Val
NP_001288218.1:p.Ala206Val
NP_001317273.1:p.Ala206Val
NP_001317275.1:p.Ala206Val
NP_001317280.1:p.Ala206Val
NP_001352705.1:p.Ala242Val
NP_001352706.1:p.Ala242Val
NP_001352707.1:p.Ala284Val
NP_001352708.1:p.Ala242Val
NP_001352709.1:p.Ala206Val
NP_001352710.1:p.Ala206Val
NP_001352711.1:p.Ala206Val
LRG_387t1:c.725C>T
LRG_387:g.24960C>T
LRG_387p1:p.Ala242Val
NC_000015.9:g.63354797C>T
NM_000366.5:c.725C>T
NM_001018005.1:c.725C>T
c.725C>T

Protein change:

A206V

Links:

dbSNP: rs397516387

NCBI 1000 Genomes Browser:

rs397516387

Molecular consequence:

NM_000366.6:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.851C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.725C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060009	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24691700, 25741868
SCV003932421	Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 12, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003932421

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 1, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A low prevalence of sarcomeric gene variants in a Chinese cohort with left ventricular non-compaction.

Tian T, Wang J, Wang H, Sun K, Wang Y, Jia L, Zou Y, Hui R, Zhou X, Song L.

Heart Vessels. 2015 Mar;30(2):258-64. doi: 10.1007/s00380-014-0503-x. Epub 2014 Apr 2.

PubMed [citation]

PMID:: 24691700

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060009.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Ala242Val variant in TPM1 has been reported in at least 5 individuals with dilated cardiomyopathy (DCM; Walsh 2017 PMID: 27532257, Van Lint 2019 PMID: 30847666, Khan 2022 PMID: 34935411, LMM data), in at least 2 individuals with left ventricular non-compaction (LVNC; Tian 2015 PMID: 24691700, Li 2018 PMID: 30371277, Miszalski-Jamka 2018 PMID: 28798025) and in 1 individual with left ventricular dysfunction and unspecified cardiomyopathy in whom the variant occurred de novo (Invitae Personal Communication 2023). In one of individuals with DCM, this variant was also identified in an affected relative with DCM (LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43437) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS2_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, SCV003932421.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine