NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 25, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000628877.15

Allele description [Variation Report for NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys)]

NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys)

Gene:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys)

Other names:

NM_000257.3(MYH7):c.3133C>T; NM_000257.4(MYH7):c.3133C>T

HGVS:

NC_000014.9:g.23422292G>A
NG_007884.1:g.18370C>T
NM_000257.4:c.3133C>TMANE SELECT
NP_000248.2:p.Arg1045Cys
LRG_384t1:c.3133C>T
LRG_384:g.18370C>T
NC_000014.8:g.23891501G>A
NM_000257.2:c.3133C>T
NM_000257.3:c.3133C>T

Protein change:

R1045C

Links:

dbSNP: rs45611033

NCBI 1000 Genomes Browser:

rs45611033

Molecular consequence:

NM_000257.4:c.3133C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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
SCV000204029	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Apr 15, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 27600940, 27247418, 27483260, 27532257, 24510615, 28005231, 18533079, 20215591, 21483645, 24033266
SCV000564441	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Uncertain significance (Aug 25, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000749785	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26199943, 27247418, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204029

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Apr 15, 2020)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000564441

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Uncertain significance
(Aug 25, 2021)

germline

curation

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

Citation Link,

SCV000749785

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2024)

germline

clinical testing

PubMed (4)
[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	7	3	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.

Cecconi M, Parodi MI, Formisano F, Spirito P, Autore C, Musumeci MB, Favale S, Forleo C, Rapezzi C, Biagini E, Davì S, Canepa E, Pennese L, Castagnetta M, Degiorgio D, Coviello DA.

Int J Mol Med. 2016 Oct;38(4):1111-24. doi: 10.3892/ijmm.2016.2732. Epub 2016 Sep 7.

PubMed [citation]

PMID:: 27600940
PMCID:: PMC5029966

A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.

Rubattu S, Bozzao C, Pennacchini E, Pagannone E, Musumeci BM, Piane M, Germani A, Savio C, Francia P, Volpe M, Autore C, Chessa L.

Int J Mol Sci. 2016 Jul 30;17(8). doi:pii: E1239. 10.3390/ijms17081239.

PubMed [citation]

PMID:: 27483260
PMCID:: PMC5000637

See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204029.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (10)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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		7	not provided	3	not provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564441.5

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

Description

The NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID: 27532257; Michels 2017 PMID:28005231) and in an additional individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052). This variant was identified in 0.00152% (FAF 95% CI; 5/129168) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000749785.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1045 of the MYH7 protein (p.Arg1045Cys). This variant is present in population databases (rs45611033, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26199943, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177753). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26199943, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Nov 3, 2024

ClinVar

Relating variation to medicine