rs727504238

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1727A>G(p.His576Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.71

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 15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 14-23427746-T-C is Pathogenic according to our data. Variant chr14-23427746-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23427746-T-C is described in Lovd as [Pathogenic]. Variant chr14-23427746-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.1727A>G	p.His576Arg	missense_variant	16/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.1727A>G	p.His576Arg	missense_variant	15/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1727A>G	p.His576Arg	missense_variant	16/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251494

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727248

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:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000852

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 576 of the MYH7 protein (p.His576Arg). This variant is present in population databases (rs727504238, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15856146, 19666645, 20646679, 24111713, 27247418, 27532257, 28615295, 30847666, 30868567, 32894683, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 177625). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 15, 2019	The p.His576Arg variant in MYH7 has been reported in at least 8 individuals and 1 family member with HCM (Perrot 2005, Michels 2009, Van der Werf 2010, Homburger 2016, LMM data). This variant has also been reported in ClinVar (Variation ID: 177625) and has been identified in 0.004% (1/24950) of African chromosomes and 0.003% (4/126704) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org;). 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 addition, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.His576Arg variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM1, PM2, PP3. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jan 16, 2019	This MYH7 His576Arg variant has previously been observed in unrelated HCM cases (Perrot et al., 2005; Michels et al., 2009; van der Werf et al., 2010; Berge & Leren, 2014; Alfares et al., 2015). Segregation data is limited, however, Michels M, et al. (2009) identified this variant in one HCM index case as well as one family member that fulfilled diagnostic criteria for HCM. Van der Werf C, et al. (2010) identified MYH7 His576Arg in a HCM family with a sudden unexplained death event (note:this family also carries a known pathogenic TNNT2 Arg102Trp variant). We have identified MYH7 His576Arg in one HCM proband with no family history of disease. Genetic analysis of parental samples reveal the presence of the variant in the mother, who is hypertensive and has mild concentric hypertrophy and does not meet the diagnostic criteria for HCM. This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.000018. 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. In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2), has been reported in at least 6 HCM probands (PS4_Moderate) and multiple in silico tools predict this variant to have a deleterious affect (PP3), therefore we classify MYH7 His576Arg as "likely pathogenic". -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces histidine with arginine at codon 576 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 15856146, 19666645, 20646679, 24111713, 27247418, 27532257, 2840870, 28615295, 30847666, 33673806, 34542152; van der Werf 2010, dissertation, University of Virginia), and in an individual affected with an unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 5/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2024	Variant summary: MYH7 c.1727A>G (p.His576Arg) 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. The variant allele was found at a frequency of 1.6e-05 in 251494 control chromosomes. c.1727A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples, Walsh_2017, Ho_2018, Homburger_2017, VanVelzen_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 30297972, 27247418, 29661763). ClinVar contains an entry for this variant (Variation ID: 177625). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 04, 2023	This missense variant replaces histidine with arginine at codon 576 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 15856146, 19666645, 20646679, 24111713, 27247418, 27532257, 2840870, 286152958, 30847666, 33673806, 34542152; van der Werf 2010, dissertation, University of Virginia), and in an individual affected with an unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 5/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 12, 2018	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 08, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24111713, 27532257, 25611685, 15856146, 22958901, 20646679, 27247418, 28615295, 24835277, 23408646, 28606303, 28408708, 24033266, 27476098, 30645170, 30868567, 30847666, 31447099, 33065066, 32894683, 33673806, 29300372, 34542152, 34495297, 35653365, 36136372, 36264615, 36243179, 19666645) -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 10, 2020	- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2023

The p.H576R variant (also known as c.1727A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1727. The histidine at codon 576 is replaced by arginine, an amino acid with highly similar 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 variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8; van der Werf C et al. Heart Rhythm, 2010 Oct;7:1383-9; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.95

MVP

0.96

MPC

2.3

ClinPred

0.86

GERP RS

4.8

Varity_R

0.97

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

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