rs121913631

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000257.4(MYH7):c.2722C>G(p.Leu908Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,104 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L908M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 2.98

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23424107-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2763277.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 14-23424107-G-C is Pathogenic according to our data. Variant chr14-23424107-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14097.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23424107-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2722C>G	p.Leu908Val	missense_variant	23/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.2722C>G	p.Leu908Val	missense_variant	22/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2722C>G	p.Leu908Val	missense_variant	23/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2722C>G (p.Leu908Val) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1638703; PMID:8483915 PMID:12473556; PMID:12975413; PMID:27532257; Partners LMM ClinVar SCV000059471.5; AGCMC Sydney ClinVar SCV000692499.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:1638703; PMID:8483915; Partners LMM ClinVar SCV000059471.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 908 of the MYH7 protein (p.Leu908Val). This variant is present in population databases (rs121913631, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1638703, 8483915, 10725281, 12473556, 12975413, 15358028, 15858117, 18403758, 21642240; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14097). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 8483915, 9172070, 11227787, 15528230). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2017	The p.Leu908Val variant in MYH7 has been well established as pathogenic for HCM. It has been reported in many families with HCM and segregated with disease in > 50 affected relatives (Epstein 1992, al-Mahdawi 1993, Cuda 1993, Rayment 1995, W oo 2003, Van Driest 2002, Fananapazir 1993, Alpert 2005, Van Driest 2004). In ad dition, studies have shown that this variant may impact protein function (Cuda 1 993, Alpert 2005). This variant has been identified in 1/14560 European chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org /; dbSNP rs121913631). In summary, the p.Leu908Val variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon recurrence in aff ected individuals, segregation studies, extremely low frequency in the general p opulation and functional evidence. ACMG/AMP Criteria: PS4, PP1_Strong; PS3_Suppo rting; PM2; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 28, 2023	This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 15528230, 1638703, 8435239, 8483915, 10725281, 12473556, 15858117, 18403758, 24510615, 25351510, 26914223, 27247418, 27532257). This variant has been shown to segregate with hypertrophic cardiomyopathy in studies of two large families with 50-60% penetrance in adults and mild prognosis (PMID: 15528230, 1638703). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	Reported in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and in the published literature (Epstein et al., 1992; Atiga et al., 2000; Van Driest et al., 2002; Woo et al., 2003; Alpert et al., 2005; Morita et al., 2008; Rodriguez et al., 2011; Pan et al., 2012; Kapplinger et al., 2014; Murphy et al., 2016; Marian et al., 2018; Mattivi et al., 2020; Burstein et al., 2021; Hathaway et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated L908V increases the velocity of actin filament movement in the in vitro motility assays performed using cardiac or skeletal muscle tissue from L908V heterozygous individuals (Palmiter et al., 2000; Alpert et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9172070, 20560001, 26914223, 8514894, 21642240, 11227787, 10615387, 7731997, 12881443, 23074333, 12473556, 15858117, 18480046, 21310275, 12428185, 9475582, 12975413, 15358028, 24510615, 12820698, 8435239, 1638703, 8483915, 15528230, 28166811, 27532257, 25351510, 27247418, 28606303, 18403758, 29300372, 10725281, 31324451, 31447099, 29540445, 33673806, 32746448, 31006259, 34135346, 32894683, 31996208, 8281650, 31905684, 22555271, 21135372) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 03, 2014	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. GBased on the strong case data, segregation data, and absence in large population samples, we consider it very likely disease causing. Per ClinVar, both LMM (SCV000059471) and Emory (SCV000110306) consider it pathogenic. This variant has been reported in at least 18 unrelated cases of HCM (including the cases in our center). There is very strong segregation data in 3 families and good functional data available. We have seen this variant in two unrelated patients with HCM in our center. Epstein et al. (1992) reported this variant in a very large kindred with very strong segregation data: Leu908Val was present in all 19 affected members of the family, who spanned 3 generations [Fananapazir et al. (1993) appears to discuss this same family.] Van Driest et al. (2002) identified it in 3 unrelated HCM patients at the Mayo Clinic. The same group later reported 8 HCM patients with this variant from their cohort; presumably 3 of these cases are redundant (Bost et al 2014). Van Driest et al. (2004) reported it in 4 unrelated patients, but it’s unclear if these include the 3 from 2002. al-Mahdawi et al. (1993) identified it in one HCM family. Mohiddin et al. (2003) found it in two unrelated HCM cases. Woo et al. (2003) found it in 3 separate families. In one family it segregated with disease in 8 family members from 3 generations (some of them 4th degree relatives). Alpert et al. (2005) found Leu908Val in a family that also carried an Asp906Gly variant in trans—the result of two brothers in one HCM family marrying two sisters in another HCM family. Among family members with only the Leu908Val variant, it segregated with disease in 21 family members. Two individuals with both mutations developed severe HCM. Yu et al. (2005) found it in an Australian family. Morita et al. (2008 + supplemental data) found it in three unrelated HCM cases. Variation at nearby codons of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ala901Gly, Glu903Lys (Van Driest et al. 2004), Cys905Phe and Asp906Gly (Harvard Sarcomere Protein Gene Mutation Database). I could find no other variants at the same codon (ClinVar, Bos et al 2014 (Mayo cohort of >1000 cases, dbSNP; as of 8 Oct 2014). Mutationtaster predicts it to be disease causing and PolyPhen2 predicts it to be possibly damaging. There is functional data available: Cuda et al. (1993, 1997) took skeletal muscle biopsies from HCM patients with this variant, and showed that the mutant cardiac myosin is also present in skeletal muscle and has abnormal function in an in vitro assay in which actin filaments are translocated by myosin bound to a coverslip surface. Fananapazir et al. (1993) analyzed skeletal muscle biopsies from HCM patients, and found 10 of 13 patients with the L908V mutation to have a myopathy resembling central core disease: a non-progressive skeletal myopathy characterized by loss of mitochondria. Palmiter et al. (2000) found the variant to alter the kinetics of the myosin cross-bridge cycle. Alpert et al. (2005) found Leu908Val to increase the velocity of actin translocation by myosin (isolated from HCM patient muscle biopsies) in vitro. This is a conservative amino acid change from a nonpolar Leucine to a nonpolar Valine. The Leucine at codon 908 is completely conserved across 44 vertebrate species examined. Surrounding residues are also highly conserved. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995) localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). In total the Leu908Val variant has not been s -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 15528230, 1638703, 8435239, 8483915, 10725281, 12473556, 15858117, 18403758, 24510615, 25351510, 26914223, 27247418, 27532257). This variant has been shown to segregate with hypertrophic cardiomyopathy in studies of two large families with 50-60% penetrance in adults and mild prognosis (PMID: 15528230, 1638703). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2021	Variant summary: MYH7 c.2722C>G (p.Leu908Val) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251552 control chromosomes. c.2722C>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Epstein_1992, VanDriest_2002, Morita_2008, Alpert_2005, Alpert_2005, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The rate of translocation of acting filaments as measured by in-vitro motility assays was 35% of wild-type levels (Cuda_1993). Subsequently, a gain of function effect was observed as an increase in actin filament velocity in the in-vitro motility assay (Palmiter_2000) and an increase in actin sliding velocity (Alpert_2005). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel) have submitted 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. -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1993	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 10, 2017	The MYH7 Leu908Val variant has been reported in more than 15 HCM probands (see literature), and in particular has been found to cosegregate with disease in a few large families (Alpert NR, et al., 2005; Woo A, et al., 2003; Epstein ND, et al., 1992). In vitro assays suggest that the variant may impact myosin cross-bridge kinetics (Palmiter et al., 2000) and increase the velocity by which myosin translocated actin (Alpert NR, et al., 2005). The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the 1000 genomes project (http://www.1000genomes.org/). We identified this variant in an HCM proband with a family history of disease, however segregation studies were not possible. Computational tools SIFT, PolyPhen-2, MutationTaster predict that this variant is deleterious. In summary, based on the large amount of probands reported with this variant, the strong segregation data, in vitro assays indicative of a functional effect, rarity in the general population and in silico tools predicting a deletrious effect, we classify the MYH7 Leu908Val variant "pathogenic". -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

The p.L908V pathogenic mutation (also known as c.2722C>G), located in coding exon 21 of the MYH7 gene, results from a C to G substitution at nucleotide position 2722. The leucine at codon 908 is replaced by valine, 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 alteration has been reported in families with hypertrophic cardiomyopathy (HCM) and strongly segregated with disease, though incomplete penetrance and a low incidence of sudden death were noted (Epstein ND et al. Circulation. 1992;86(2):345-52; al-Mahdawi S et al. Br Heart J. 1993;69(2):136-41; Woo A et al. Heart. 2003;89(10):1179-85). This alteration has also been reported in additional HCM cohorts (Lopes LR et al. Heart. 2015;101(4):294-301; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A.. 2016;113(24):6701-6; Walsh R et al. Genet. Med. 2017 02;19(2):192-203). In vitro motility assays showed an increase in actin filament velocities and gain of function (Palmiter KA et al. J Muscle Res Cell Motil. 2000;21(7):609-20; Alpert NR et al. Am J Physiol Heart Circ Physiol. 2005;288(3):H1097-102). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.56

MutPred

0.72

Gain of methylation at K912 (P = 0.0627);

MVP

0.97

MPC

2.1

ClinPred

0.98

GERP RS

5.5

Varity_R

0.54

gMVP

1.0

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