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

gnomAD frequency: 0.00001  dbSNP: rs121913627

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-04-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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, 30025578, 17383184, 15858117, 8981935, 30554920, 29398688, 31513939, 31996869, 32217077, 32344918, 31983222, 31737537, 12707239, 8281650, 31589614, 33673806, 32894683, 9172070, 29300372)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000015147	SCV000212626	pathogenic	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	2022-10-24	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 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 mutation 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	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 606 of the MYH7 protein (p.Val606Met). This variant is present in population databases (rs121913627, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1552912, 9271024, 11133230, 11377367, 15858117, 20624503, 20819418, 24111713). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14091). 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: 9172070, 9826622, 18020371, 21769673, 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 Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV000223823	SCV001747705	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	MYH7: PP1:Strong, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525146	SCV002042258	pathogenic	Cardiomyopathy	2019-12-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223823	SCV002048322	pathogenic	not provided	2021-05-22	criteria provided, single submitter	clinical testing	The MYH7 c.1816G>A; p.Val606Met variant (rs121913627) is reported in the literature in numerous individuals and families affected with hypertrophic cardiomyopathy (HCM) (Arad 2014, Greber-Platzer 2001, Havndrup 2001, Watkins 1992, Zheng 2010). This variant has been found to co-segregate with disease in multiple families, although it also exhibits variable penetrance and expressivity (Arad 2014, Greber-Platzer 2001, Havndrup 2001, Watkins 1992, Zheng 2010). This variant is found on only two chromosomes in the Genome Aggregation Database (2/282868 alleles), indicating it is not a common polymorphism. The valine at codon 606 is highly conserved, it occurs in the myosin motor domain, and functional studies suggest the variant protein has altered kinetics compared to wildtype protein (Roopnarine 1998). A mouse model expressing the p.Val606Met variant exhibits largely normal cardiac function alone but develops mild HCM in response to cyclosporine and leads to a severe HCM phenotype in combination with another MYH7 variant (Blankenburg 2014). Based on available information, the p.Val606Met variant is considered to be pathogenic. References: Arad M et al. Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic. Isr Med Assoc J. 2014;16(11):707-713. Blankenburg R et al. Beta-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res. 2014;115(2):227-237. Greber-Platzer S et al. Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children. J Mol Cell Cardiol. 2001;33(1):141-148. Havndrup O et al. The Val606Met mutation in the cardiac beta-myosin heavy chain gene in patients with familial hypertrophic cardiomyopathy is associated with a high risk of sudden death at young age. Am J Cardiol. 2001;87(11):1315-1317. Roopnarine O and Leinwand LA. Functional analysis of myosin mutations that cause familial hypertrophic cardiomyopathy. Biophys J. 1998;75(6):3023-3030. Watkins H et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992;326(17):1108-1114. Zheng DD et al. Mutations in the beta-myosin heavy chain gene in southern Chinese families with hypertrophic cardiomyopathy. J Int Med Res. 2010;38(3):810-820.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015147	SCV002767875	pathogenic	Hypertrophic cardiomyopathy 1	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID 29300372). (I) 0115 - Variants in this gene are known to have variable expressivity. Patients with this specific variant have been reported with varying severity, from mild hypertrophic cardiomyopathy to sudden cardiac death (ClinVar). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional myosin head domain (PMID 29300372). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times, and in over 20 patients with hypertrophic cardiomyopathy with varying severity (ClinVar, LOVD, PMID: 30775854). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003320032	SCV003835645	pathogenic	Myosin storage myopathy	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320032	SCV003835646	pathogenic	Myosin storage myopathy	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147290	SCV003835647	pathogenic	Dilated cardiomyopathy 1S	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147293	SCV003836198	pathogenic	MYH7-related skeletal myopathy	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147294	SCV003836364	pathogenic	Myopathy, myosin storage, autosomal recessive	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000015147	SCV003836422	pathogenic	Hypertrophic cardiomyopathy 1	2022-04-27	criteria provided, single submitter	clinical testing
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV000035750	SCV003932409	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
OMIM	RCV000015147	SCV000035404	pathogenic	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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000223823	SCV001956095	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000223823	SCV001964171	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV004545730	SCV002075188	not provided	MYH7-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-18-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.