ClinVar Miner

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

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Total submissions: 12
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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 2011-04-15 criteria provided, single submitter clinical testing The Val606Met variant has been reported in the literature in 24 probands with HC M where it was absent from 900 control chromosomes and has been demonstrated to segregate with disease in multiple families (Watkins 1992, Solomon 1993, Fananap azir 1994, Marian 1995, Richard 2003, Greber-Platzer 2001, Blair 2001, Havndrup 2001, Havndrup 2003, Ingles 2005, Jacques 2008, Zheng 2010). It should be noted however, that this variant is associated with variable presentation, including t he age at onset and with different outcomes in different families (Fananapazir 1 994, Nakajima-Taniguchi 1995, Fananapazir 1997, Havndrup 2001). In summary, the Val606Met variant meets our criteria for pathogenicity ( g/LMM) based on the frequency in affected individuals, absence from controls, an d segregation studies.
Blueprint Genetics RCV000035750 SCV000188795 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000223823 SCV000208754 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing The V606M pathogenic variant in the MYH7 gene has previously been reported multiple times in association with HCM and was reported to segregate with disease in affected individuals from multiple unrelated families (Watkins et al., 1992; Marian et al., 1995b; Havndrup et al., 2001; Morita et al., 2008; Yuan et al., 2008; Marsiglia et al., 2013; Rubattu et al., 2016). This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to have occurred de novo in one young individual with suspected HCM. In addition, this variant has been classified in ClinVar as a pathogenic or likely pathogenic variant by multiple other clinical laboratories (ClinVar SCV000059401.4, SCV000188795.3, SCV000318971.1, SCV000219888.1, SCV000280305.1; Landrum et al., 2016). Although it has been suggested that V606M may be associated with a milder cardiomyopathy phenotype, subsequent studies have noted this variant has been associated with variable clinical phenotypes, including early onset heart failure and sudden death (Marian et al., 1995b; Havndrup et al., 2001).The V606M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the V606M variant is a conservative amino acid substitution, this variant occurs at an evolutionarily conserved position within the actin binding region of the protein (Roopnarine et al., 1998). In silico analysis predicts this variant is probably damaging to the protein/structure function. Roopnarine et al. (1998) reported that the V606M variant has a mild effect on the ATPase activity of the channel protein. Furthermore, in vitro studies by Cuda et al. (1997) demonstrated that V606M resulted in decreased actin sliding velocities.In summary, V606M in the MYH7 gene is interpreted as a pathogenic variant.
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 Strong segregation with disease (lod >3 = >10 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000473084 SCV000546283 pathogenic Hypertrophic cardiomyopathy 2019-12-03 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.
Integrated Genetics/Laboratory Corporation of America 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
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

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