ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1816G>A (p.Val606Met) (rs121913627)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000473084 SCV000059401 pathogenic Hypertrophic cardiomyopathy 2020-07-13 criteria provided, single submitter clinical testing The p.Val606Met variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 15 affected individuals from multiple families (Watkins 1992 PMID: 1552912, Solomon 1993 PMID: 8335820, Fananapazir 1994 PMID: 8281650, Marian 1995 PMID: 7789380, Richard 2003 PMID: 12707239, Greber-Platzer 2001 PMID: 11133230, Blair 2001 PMID: 11424919, Havndrup 2001 PMID: 11377367, Havndrup 2003 PMID: 12566107, Ingles 2005 PMID: 16199542, Jacques 2008 PMID: 18411228, Zheng 2010 PMID: 20819418, LMM data). It should be noted, however, that this variant is associated with variable presentation, including the age at onset and with different outcomes in different families (Fananapazir 1994 PMID: 8281650, Nakajima-Taniguchi 1995 PMID: 8788376, Fananapazir 1997 PMID: 9058851, Havndrup 2001 PMID: 11377367). It has also been identified in 0.002% (2/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 14091). Computational prediction tools and conservation analyses are consistent with pathogenicity. Animal models in mice suggest that this variant can result in HCM (Blankenburg 2014 PMID: 24829265). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS3, PS4, PP1_Strong, PM2, PP3.
Blueprint Genetics RCV000035750 SCV000188795 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000223823 SCV000208754 pathogenic not provided 2021-05-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24093860, 18403758, 27247418, 25351510, 20624503, 30775854, 24829265, 21769673, 19100006, 11377367, 1552912, 27483260, 9826622, 21310275, 27532257, 29101517, 7789380, 11133230, 20819418, 28971120, 9172070, 30025578, 17383184, 15858117, 8981935, 30554920, 29398688, 31513939, 31996869, 32217077, 32344918, 31983222, 31737537, 12707239, 31589614, 33673806)
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015147 SCV000212626 pathogenic Familial hypertrophic cardiomyopathy 1 2014-10-30 criteria provided, single submitter research This MYH7 Val606Met variant has previously been described in HCM patients. Co-segregation of this variant with disease has been demonstrated in multiple unrelated families, with complete disease penetrance observed in relatives of the proband (Watkins H., et al 1992; Fananapazir L., et al 1994; Havndrup O., et al 2001) . Disease manifestation associated with this variant are markedly variable amongst individuals and between unrelated families. Watkins H., et al (1992) report their family to have "near normal survival" whereas Havndrup O., et al (2001) report a family with the same MYH7 Val606Met mutation to have unfavourable outcomes with high risk of sudden cardiac death. We have observed the Val606Met mutation in two HCM families (Ingles J., et al 2005) and have shown that it segregates with disease. Therefore, this variant is categorised by our group as "pathogenic" based on available literature and familial segregation analysis where possible.
Ambry Genetics RCV000252267 SCV000318971 pathogenic Cardiovascular phenotype 2019-03-23 criteria provided, single submitter clinical testing The p.V606M pathogenic mutation (also known as c.1816G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1816. The valine at codon 606 is replaced by methionine, an amino acid with highly similar properties. This mutation, located in the S1-actin binding domain of MYH7, has been described in several individuals with hypertrophic cardiomyopathy (HCM); however, it initially was detected​ in 3 unrelated kindreds with familial HCM, reportedly segregating with disease in all 18 affected family members across the 3 families with a combined LOD score of 3.5 (Watkins H et al. N. Engl. J. Med.1992;326:1108-1114; Berge KE et al. Clin Genet. 2014;86(4):355-60; Bagnall RD et al. J Am Col Cardiol. 2018;72(4):419-429; Jääskeläinen P. ESC Heart Fail. 2019 Feb). One of the families originally described by Watkins et al was further described, noting that the index patient and three family members with HCM and this alteration also had distal myopathy while others had HCM only (Overeem S et al. Neuromuscul. Disord. 2007;17(6):490-493). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000473084 SCV000546283 pathogenic Hypertrophic cardiomyopathy 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 606 of the MYH7 protein (p.Val606Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in several families affected with hypertrophic cardiomyopathy (HCM) (PMID: 1552912, 11133230, 20819418) and multiple unrelated affected individuals (PMID: 15858117, 24111713, 11377367, 9271024, 20624503). ClinVar contains an entry for this variant (Variation ID: 14091). Experimental studies have shown that this missense change impairs MYH7 motility in vitro (PMID: 9172070, 9826622) and shows reduction in MYH7 protein expression in muscle biopsies of affected individuals with this variant (PMID: 18020371, 21769673). In addition, mice expressing this variant developed mild hypertrophy (PMID: 24829265). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000252267 SCV000696338 pathogenic Cardiovascular phenotype 2017-06-15 criteria provided, single submitter clinical testing Variant summary: The MYH7 c.1816G>A (p.Val606Met) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the P-loop containing nucleoside triphosphate hydrolase domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and a control cohort from the literature (0/121586 control chromosomes). The variant was reported in multiple HCM pts (associated with longer survival compared with other DVs such as R453C and R403Q) by independent literature reports. Functional studies (Blankenburg_Circulation Research_2014; Tripathi_Basic Res Cardiol_2011; Roopnarine_BJ_1998; and Cuda_JMRCM_1997) showed lower in vitro motility activity, decreased actin-activated ATPase activity, allelic imbalance, and a mouse model study showed that the variant causes very mild hypertrophic cardiomyopathy in mice, but the HCM phenotype becomes much more severe with the presence of another HCM mutation. Additionally, the variant has been found segregating with disease in several ethnically diverse families with HCM (Watkins_NEJM_1992; Arad_IMAJ_2014, for example). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. It should be noted that the variant of interest has had conflicting reports regarding phenotypic association, indicating that there is variability in the phenotypes or incomplete penetrance associated with this mutation, which could be due to the effect of modifier genes and environmental factors. However, based on the enrichment of the variant in HCM patients and functional studies, the variant is classified as pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035750 SCV000747981 likely pathogenic Primary familial hypertrophic cardiomyopathy 2016-11-25 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000473084 SCV000886784 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV001525146 SCV001735188 pathogenic Cardiomyopathy 2021-01-05 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 606 in the actin-binding 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). Functional studies have shown the mutant protein to exhibit partially reduced ATPase activity (PMID: 9826622) and motility (PMID: 9172070). This variant caused mild hypertrophic cardiomyopathy in transgenic mice (PMID: 24829265). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 11133230, 25558701, 1552912, 20819418, 21769673, 9271024, 11377367, 20624503, 24111713, 24835277, 27483260, 30775854). This variant has been shown to segregate with hypertrophic cardiomyopathy in 32 individuals from 6 different families (PMID: 1552912, 11133230, 20819418, 25558701). This variant has been identified in 2/282868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223823 SCV001747705 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
OMIM RCV000015147 SCV000035404 pathogenic Familial hypertrophic cardiomyopathy 1 2001-06-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223823 SCV000280305 pathogenic not provided 2013-10-01 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. p.Val606Met (c.1816 G>A) in MYH7 This variant has been reported in more than 17 unrelated individuals with HCM. With strong segregation data and a transgenic mouse model The Seidman team first reported the variant in three families with a Lod score of 3.5 (Watkins et al 1992), though unfortunately the authors do not report how many affected individuals had the variant in each family. The same group later published on eight affected individuals with this variant, presumably from the same three families initially reported (Solomon et al 1993). Fananapazir et al (1994) reported two additional cases with this variant with at least four family members segregating the variant and disease. Marian et al (1995) reported a family in which all 8 individuals with HCM and 1 obligate carrier carried p.Val606Met (likely the same family as reported in Abchee et al 1997, though only abstract is available). Nakajima-Taniguchi et al (1995) observed the variant in a Japanese man with HCM. Semsarian et al (1997) described an Australian patient with HCM. Greber-Platzer et al (2001) reported a family with four affected family members who all carried this variant. Havndrup et al (2001, 2003) reported a Danish family with four family members with HCM who all carried this variant. Blair et al (2001) reported a family in which two individuals with HCM had p.Val606Met. They also had p.Ala728Val and the two were thought to be in cis. Richard et al (2003) reported the variant in one HCM patient in their French cohort. Ingles et al reported the variant in a patient with HCM from their Australian cohort and based on how they label their pedigrees, this seems to be different case from the one reported by Semsarian et al (1997). Yuan et al (2008) reported a Chinese family with four affected members with p.Val606Met. Overeem et al (2007) reported a family with p.Val606Met that had both HCM and a distal skeletal myopathy. Yu et al (2005) reported the variant in an Australian patient that seems to be distinct from the Ingles et al and Semsarian et al reports. Morita et al (2008) reported the variant in a child with HCM from the American pediatric cardiomyopathy registry. Kubo et al (2007) reported the variant in a patient with HCM from their British cohort. Zheng et al (2010) reported a Chinese family in which all three members with HCM had this variant (this seems to be distinct from the family reported by Yuan et al 2008). Millat et al (2010) identified the variant in 2 individuals with HCM from their French cohort, which seems to be distinct from the case reported by Richard et al (2003). Cuda et al (1997) demonstrated that purified myosin from patients with p.Val606Met had decreased actin sliding velocities. A review by Walsh et al (2010) and a presentation by the Seidman group online both refer to a mouse model using p.Val606Met that recapitulates HCM, however I could not find the primary reference. The Valine at codon 606 is highly, though not completely conserved across species (there is a Proline at this codon in Rhesus monkeys). In silico analysis with polyphen 2 predicts the variant to be probably damaging. Another variant at the same codon has been reported in association with HCM (p.Val606Leu, Waldmuller et al 2002), as have variants at nearby codons (p.Lys611Asn (Seidman group, online), p.Asn602Ser (Marian et al 1995, Koyanagi et al 1996), p.Leu601Val (Havndrup et al 2003). The variant as absent in a total of 470 published controls including 100 (Havndrup et al 2001), 100 (Richard et al 2003), 150 (Ingles et al 2005), 120 (Yuan et al 2008). Early studies did not report control data. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5000 Caucasian and African American individuals (as of January 11th, 2012). Note that this dataset does not match the patient's ancestry (Indian and Sri Lankan).
Gharavi Laboratory,Columbia University RCV000223823 SCV000809468 pathogenic not provided 2018-09-16 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000223823 SCV001740159 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000223823 SCV001924482 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000223823 SCV001931792 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000223823 SCV001956095 pathogenic not provided no assertion criteria provided clinical testing

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