NM_000257.4:c.1954A>G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1954A>G(p.Arg652Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense, splice_region

Scores

Splicing: ADA: 0.009501

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.859

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a helix (size 16) in uniprot entity MYH7_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 14-23427242-T-C is Pathogenic according to our data. Variant chr14-23427242-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 177626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23427242-T-C is described in Lovd as [Pathogenic]. Variant chr14-23427242-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.1954A>G	p.Arg652Gly	missense_variant, splice_region_variant	Exon 17 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.1954A>G	p.Arg652Gly	missense_variant, splice_region_variant	Exon 16 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.1954A>G	p.Arg652Gly	missense_variant, splice_region_variant	Exon 17 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251392

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 05, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Arg652Gly (c.1954A>G) Given the case data, segregation, and absence in individuals not selected for having HCM, we consider this variant likely disease causing. The variant has been seen in at least 4 (and possibly 7) unrelated cases of HCM (not including this patient's family). There is moderate segregation data. There is no ClinVar entry (as of December 23rd, 2014). Ho et al (2002) reported the variant in 4 affected family members from a kindred with HCM. These presumably overlap with later reports by this group (Ho et al 2013, Valente et al 2013, Ho et al 2014)). I found an online presentation from a UK genetics group (Aberdeen) that seems to report they saw this variant in one patient with HCM. Santos et al (2012) observed the variant in one of 80 Portuguese individuals with HCM who underwent analysis of 28 HCM-associated genes. Coppini et al (2014) included three patients with HCM and this variant from their Italian cohort in a paper comparing thin and thick filament HCM. This presumably overlaps with this group's prior report(s) (Olivotto et al 2008). It is unclear whether the patients were related or unrelated. Coto et al reported the variant in 1 of 60 HCM patients who underwent MYH7 analysis. The variant was reported online in 1 of 61,081 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 23rd, 2014). Specifically, the variant was observed in 1 of 33589 individuals of European decent. The phenotype of that individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Nov 18, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R652G variant in the MYH7 gene has been reported previously in association with HCM (Coto et al., 2012; Ho et al., 2002). In the study by Coto et al., R652G was reported in one individual with HCM and was absent in 150 Caucasian controls (Coto et al., 2012). The R652G variant was also reported in one family in which R652G was present in four family members with a HCM phenotype (Ho et al., 2002). R652G results in a non-conservative amino acid substitution of a hydrophilic Arginine with a hydrophobic Glycine at a residue that is conserved across species. In silico analysis predicts R652G is probably damaging to the protein structure/function. Additionally, pathogenic variants in nearby residues (S642L, L658V, M659T, M659I, T660N) have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014), further supporting the functional importance of this region of the protein. Finally, the R652G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret the R652G variant as pathogenic. -

Hypertrophic cardiomyopathy

Pathogenic:2

May 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg652Gly variant has been reported in 2 individuals with HCM (Ho 2002, Co to 2012) and was reported to segregate with disease in 6 affected relatives (C. Seidman, pers comm). This variant has also been identified in 1/66208 of Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org), though for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Arginine (Arg) at position 652 is highly conserved in mammals and across evolut ionarily distant species and the change to glycine (Gly) was predicted to be pat hogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, this variant is located in the last three bases of the exon, which is part of the 5? splice region, though computational tools do not sugges t an impact to splicing. In summary, this variant meets our criteria to be class ified as pathogenic for HCM in an autosomal dominant manner (http://www.partners .org/personalizedmedicine/LMM) based upon segregation studies and its low freque ncy in the general population. -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 652 of the MYH7 protein (p.Arg652Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22429680, 22765922, 23549607, 27247418, 27532257, 28790153). ClinVar contains an entry for this variant (Variation ID: 177626). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Nov 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.1954A>G (p.Arg652Gly) is located near a canonical splice site and results in a non-conservative amino acid change located in the myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251392 control chromosomes (gnomAD). c.1954A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy, including individuals with a positive family history and at least one family in which it segregated with the disease phenotype (e.g. Ho_2002, Olivotto_2008, Coppini_2014, Ross_2017, Walsh_2017, Bagnall_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a significant clustering of missense pathogenic variants has been identified in the myosin head domain in HCM cases (Walsh_2017) and another variant affecting the same amino acid (p.Arg652Lys) has also been identified in individuals with HCM (HGMD database) and has been classified as pathogenic in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 36252119, 25524337, 12081993, 30297972, 18533079, 28615295, 27532257). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Apr 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R652G pathogenic mutation (also known as c.1954A>G), located in coding exon 15 of the MYH7 gene, results from an A to G substitution at nucleotide position 1954. The arginine at codon 652 is replaced by glycine, an amino acid with dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration was first reported as detected in four affected individuals in one family from a hypertrophic cardiomyopathy (HCM) cohort (Ho CY et al. Circulation, 2002 Jun;105:2992-7). This alteration has also been reported in additional individuals from several HCM cohorts (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Santos S et al. BMC Med. Genet., 2012 Mar;13:17; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10(2)). Another alteration at the same codon, p.R652K (c.1955G>A), has been reported to segregate with HCM in several families (Antoniutti G et al. Genes (Basel), 2022 Feb;13). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

May 29, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This MYH7 Arg652Gly variant has previously been described in several HCM probands (Ho CY et al., 2002; Santos S, et al., 2012; Coto E et al., 2012; Walsh R, et al., 2017). Familial segregation from Ho (2002) identified the variant in 4 affected individuals. We have identified this variant in 2 HCM probands. The first is an isolated HCM case, who has no known family history of disease. The second proband harbours another variant (MYBPC3 Leu994Phe) and both variants have been found to segregate to an affected family member. MYH7 Arg652Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and is a singleton event (MAF= 0.000008) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). In silico tools SIFT, PolyPhen-2, MutationTaster and CADD predict the 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 identified in multiple HCM cases (PS4), is located in a mutational hotspot (PM1), is rare in the general population (PM2), segregates with disease (PP1) and in silico tools predict a deleterious effect (PP3), therefore we classify MYH7 Arg652Gly as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.64

Vest4

0.96

MutPred

0.81

Loss of MoRF binding (P = 0.0145);

MVP

0.99

MPC

2.4

ClinPred

0.99

GERP RS

2.7

Varity_R

0.85

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0095

dbscSNV1_RF

Benign

0.086

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over