rs121913631

Positions:

• chr14-23424107-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4 PP3 PM1 PM2 PP1_Strong

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA012953/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

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: 4 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 2 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

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.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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 -

not provided Pathogenic:3

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 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 16, 2015	- -

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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 04, 2015	- -

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	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.72		Gain of methylation at K912 (P = 0.0627);
MVP		0.97
MPC		2.1
ClinPred		0.98	D
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

Other links and lift over

dbSNP: rs121913631; hg19: chr14-23893316;