NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp) AND Hypertrophic cardiomyopathy 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 6, 2021
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:: RCV002466449.3

Allele description [Variation Report for NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)]

NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)

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.2221G>T (p.Gly741Trp)

Other names:

p.G741W:GGG>TGG; NM_000257.3(MYH7):c.2221G>T

HGVS:

NC_000014.9:g.23425760C>A
NG_007884.1:g.14902G>T
NM_000257.4:c.2221G>TMANE SELECT
NP_000248.2:p.Gly741Trp
LRG_384t1:c.2221G>T
LRG_384:g.14902G>T
NC_000014.8:g.23894969C>A
NM_000257.2:c.2221G>T
NM_000257.3:c.2221G>T
P12883:p.Gly741Trp

Protein change:

G741W

Links:

UniProtKB: P12883#VAR_004589; dbSNP: rs121913632

NCBI 1000 Genomes Browser:

rs121913632

Molecular consequence:

NM_000257.4:c.2221G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 1
Synonyms:: Familial hypertrophic cardiomyopathy 1; MYH7-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0008647; MedGen: C3495498; OMIM: 192600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212638	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2018)	germline	research	PubMed (13) [See all records that cite these PMIDs] 24093860, 15563892, 12707239, 15856146, 15358028, 8533830, 8483915, 23074333, 22112859, 27532257, 28408708, 24510615, 25741868
SCV002761790	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005398121	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24714796, 27532257, 29300372, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212638

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 2, 2018)

germline

research

PubMed (13)
[See all records that cite these PMIDs]

SCV002761790

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2021)

germline

clinical testing

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

SCV005398121

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2021)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy.

Marsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, Pedrosa RP, Barbosa-Ferreira JM, Mady C, Krieger JE, Arteaga-Fernandez E, Pereira Ada C.

Am Heart J. 2013 Oct;166(4):775-82. doi: 10.1016/j.ahj.2013.07.029. Epub 2013 Sep 18.

PubMed [citation]

PMID:: 24093860

Mutations profile in Chinese patients with hypertrophic cardiomyopathy.

Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J, Hui R.

Clin Chim Acta. 2005 Jan;351(1-2):209-16.

PubMed [citation]

PMID:: 15563892

See all PubMed Citations (15)

Details of each submission

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000212638.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (13)

Description

This MYH7 Gly741Trp variant has been reported in mutliple HCM cases (Arai S, et al., 1995; Perrot A, et al., 2005; Otsuka H, et al., 2012; Santos S, et al., 2012; Pan S, et al., 2012; Kapplinger JD, et al., 2014; Walsh R, et al., 2017), and the variant was shown to segregate with disease in affected family members (Arai S, et al., 1995; Perrot A, et al., 2005). Interestingly, a variant at the same position resulting in a different amino acid change, Gly741Arg, has extensively reported in HCM cases (Fananapazir L, et al., 1993; Richard P, et al., 2003; Van Driest SL, et al., 2004; Song L, et al., 2005; Kaski JP, et al., 2009; Marsiglia JD, et al., 2013; Kapplinger JD, et al., 2014; Walsh R, et al., 2017). The MYH7 Gly741Trp variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), and the 1000 genomes project (http://www.1000genomes.org/). We have identified this variant in 5 HCM Probands. All four probands have a family history of disease, but segregation was only possible in 3 of these families and we found this variant to segregate in total of 4 affected first degree family members. In silico tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 15 unrelated probands (PS4), segregates with disease in multiple families (PP1_strong), is located in a mutational hotspot (PM1), is rare in the general population (PM2), affects the same amino acid as another disease-causing variant (PM5), and is predicted to be deleterious by multiple in silico tools (PP3), therefore we classify MYH7 Gly741Trp as 'Pathogenic'.

#	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

From Genetics and Molecular Pathology, SA Pathology, SCV002761790.1

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398121.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the myosin motor domain (NCBI, PMID: 29300372). (SP) 0702 - Another missense variant comparable to the one identified in this case has strong previous evidence for pathogenicity. An alternative change to arginine at the same residue has previously been reported as pathogenic in more than ten individuals with HCM (ClinVar, PMID: 27532257). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in more than ten individuals with HCM (ClinVar, VCGS, PMID: 27532257). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Apr 13, 2025

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