ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2722C>G (p.Leu908Val) (rs121913631)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000458449 SCV000564438 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation 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; 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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000458449 SCV000059471 pathogenic Hypertrophic cardiomyopathy 2017-02-21 criteria provided, single submitter clinical testing 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, /; 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.
GeneDx RCV000078452 SCV000208505 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The L908V pathogenic variant in the MYH7 gene has been previously reported in multiple unrelated individuals with HCM (Epstein et al., 1992; Van Driest et al., 2002; Woo et al., 2003; Alpert et al., 2005; Rodriguez et al., 2011; Pan et al., 2012; Kapplinger et al., 2014; Murphy et al., 2016). This variant was also found to segregate with HCM in numerous affected relatives from multiple different families (Epstein et al., 1992; Woo et al., 2003; Alpert et al., 2005; Rodriguez et al., 2011; Pan et al., 2012). Additionally, this variant has been observed in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. Furthermore, L908V is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Though L908V variant is a conservative amino acid substitution, functional studies have demonstrated that 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). Finally, a different missense variant at the same residue (L908P) and variants in nearby residues (E903K, E903G, R904C, R904H, D906G) have been reported at GeneDx and/or in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.
Blueprint Genetics RCV000035820 SCV000264086 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247943 SCV000319946 pathogenic Cardiovascular phenotype 2019-04-09 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078452 SCV000331349 pathogenic not provided 2015-09-16 criteria provided, single submitter clinical testing
Invitae RCV000458449 SCV000546238 pathogenic Hypertrophic cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 908 of the MYH7 protein (p.Leu908Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15858117, 15358028, 10725281, 18403758, 12473556, Invitae) and has been shown to segregate with disease in families (PMID: 12975413, 8483915, 21642240, 1638703). ClinVar contains an entry for this variant (Variation ID: 14097). Experimental studies have demonstrated that this missense change is deleterious (PMID: 8483915, 9172070, 11227787, 15528230). In summary, this variant is a rare missense change that is absent from population databases, has been reported in many individuals and families affected with HCM, and has been shown to affect protein function. For these reasons, it has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015153 SCV000692499 pathogenic Familial hypertrophic cardiomyopathy 1 2017-03-10 criteria provided, single submitter research 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 (, as well as the 1000 genomes project ( 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".
Integrated Genetics/Laboratory Corporation of America RCV000035820 SCV000917841 pathogenic Primary familial hypertrophic cardiomyopathy 2018-07-10 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2722C>G (p.Leu908Val) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31070 control chromosomes (gnomAD and publications). The variant, c.2722C>G, has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (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. At least one publication reports experimental evidence evaluating an impact on protein function (Palmiter_2000, Alpert_2005). The most pronounced variant effect results in 30%-50% of normal activity (Cuda_1993). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV001177579 SCV001341816 pathogenic Cardiomyopathy 2019-11-26 criteria provided, single submitter clinical testing
OMIM RCV000015153 SCV000035410 pathogenic Familial hypertrophic cardiomyopathy 1 1993-05-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000078452 SCV000280334 pathogenic not provided 2014-10-03 no assertion criteria provided 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. 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 seen in ~7341 published controls and publicly available population datasets. No variation at codon 908 is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian African American individuals (as of 1/15/2012). It was not observed in 841 published controls: Epstein et al. (1992) did not observe the variant in 50 controls. Van Driest et al. (2002) did not report controls. al-Mahdawi et al. (1993) did not find it in 5 controls. Mohiddin et al. (2003) did not find it in 200 controls. Woo et al. (2003) did not find it in 106 controls. Van Driest et al. (2004) did not observe the variant in 100 Caucasian and 100 African American controls (likely redundant with Bos et al 2014). Yu et al. (2005) did not find it in 100 Australian controls matched for ethnicity. Morita et al. (2008) did not find it in 180 ethnicity-matched controls. The Leu908Val variant is present in dbSNP as rs121913631 (“probable-pathogenic”). It was submitted by the OMIM staff at Johns Hopkins.

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