NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 23, 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:: RCV000695968.8

Allele description [Variation Report for NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)]

NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)

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.688G>A (p.Asp230Asn)

Other names:

p.D230N:GAC>AAC

HGVS:

NC_000015.10:g.63062263G>A
NG_007557.1:g.24625G>A
NM_000366.6:c.688G>A
NM_001018004.1:c.688G>A
NM_001018004.2:c.688G>A
NM_001018005.2:c.688G>AMANE SELECT
NM_001018006.2:c.688G>A
NM_001018007.2:c.688G>A
NM_001018008.2:c.580G>A
NM_001018020.2:c.688G>A
NM_001301244.2:c.688G>A
NM_001301289.2:c.580G>A
NM_001330344.2:c.580G>A
NM_001330346.2:c.580G>A
NM_001330351.2:c.580G>A
NM_001365776.1:c.688G>A
NM_001365777.1:c.688G>A
NM_001365778.1:c.814G>A
NM_001365779.1:c.688G>A
NM_001365780.1:c.580G>A
NM_001365781.2:c.580G>A
NM_001365782.1:c.580G>A
NP_000357.3:p.Asp230Asn
NP_001018004.1:p.Asp230Asn
NP_001018005.1:p.Asp230Asn
NP_001018006.1:p.Asp230Asn
NP_001018007.1:p.Asp230Asn
NP_001018008.1:p.Asp194Asn
NP_001018020.1:p.Asp230Asn
NP_001288173.1:p.Asp230Asn
NP_001288218.1:p.Asp194Asn
NP_001317273.1:p.Asp194Asn
NP_001317275.1:p.Asp194Asn
NP_001317280.1:p.Asp194Asn
NP_001352705.1:p.Asp230Asn
NP_001352706.1:p.Asp230Asn
NP_001352707.1:p.Asp272Asn
NP_001352708.1:p.Asp230Asn
NP_001352709.1:p.Asp194Asn
NP_001352710.1:p.Asp194Asn
NP_001352711.1:p.Asp194Asn
LRG_387t1:c.688G>A
LRG_387:g.24625G>A
LRG_387p1:p.Asp230Asn
NC_000015.9:g.63354462G>A
NM_000366.5:c.688G>A
NM_001018005.1:c.688G>A
c.688G>A
p.(Asp230Asn)

Protein change:

D194N

Links:

Leiden Muscular Dystrophy (TPM1): TPM1_00015; dbSNP: rs199476317

NCBI 1000 Genomes Browser:

rs199476317

Molecular consequence:

NM_000366.6:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.580G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824509	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20117437, 27532257, 23539503, 25242052, 25548289, 28600229, 28603979, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824509

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2023)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy.

Lakdawala NK, Dellefave L, Redwood CS, Sparks E, Cirino AL, Depalma S, Colan SD, Funke B, Zimmerman RS, Robinson P, Watkins H, Seidman CE, Seidman JG, McNally EM, Ho CY.

J Am Coll Cardiol. 2010 Jan 26;55(4):320-9. doi: 10.1016/j.jacc.2009.11.017.

PubMed [citation]

PMID:: 20117437
PMCID:: PMC3000630

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824509.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 230 of the TPM1 protein (p.Asp230Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20117437, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 23539503, 25242052, 25548289, 28600229, 28603979). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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