ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.958G>A (p.Val320Met) (rs376897125)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158772 SCV000208707 uncertain significance not specified 2017-01-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The V320M variant has previously been reported in association with HCM (Havndrup et al., 2003; Fokstuen et al., 2011; Brito et al., 2012; Marsiglia et al., 2013; Alvarez-Acosta et al., 2014). This variant was first reported in one Danish individual with HCM who required septal myocardial ablation (Havndrup et al., 2003). However, Havndrup et al. (2003) also identified V320M in the proband's brother, who had a normal cardiac exam, and in an asymptomatic child who had a suspicious septal bulb but was found to be asymptomatic after follow-up at 26 years-old (Jensen et al., 2013). Most recently, Alvarez-Acosta et al. (2014) identified V320M in one Spanish index patient with HCM who also harbored a variant in MYL2. The proband's cousin was less severely affected and harbored only the MYL2 variant (Alvarez-Acosta et al., 2014). The V320M variant was not observed at a significant frequency 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V320M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Despite the fact that several publications describe an association between the V320M variant in the MYH7 gene and HCM, segregation with disease was not reported. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the V320M variant.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201440 SCV000256154 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000549661 SCV000623763 likely pathogenic Hypertrophic cardiomyopathy 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 320 of the MYH7 protein (p.Val320Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs376897125, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12566107, 20031602, 21239446, 22857948, 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 161328). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been reported in several affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000549661 SCV000710839 likely pathogenic Hypertrophic cardiomyopathy 2019-02-08 criteria provided, single submitter clinical testing The p.Val320Met variant in MYH7 has been reported in over 20 individuals with hy pertrophic cardiomyopathy (HCM) (Brito 2012, Fokstuen 2011, Havndrup 2003, Hombu rger 2016, Jensen 2013, Marsiglia 2013, Walsh 2017) and segregated with disease in at least one affected individuals from one family (Havndrup 2003). It has als o been identified in 1/16250 African chromosomes by gnomAD (http://gnomad.broadi nstitute.org). This variant has also been reported in ClinVar (Variation ID: 161 328). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. This variant lies in the head region of the protei n and missense variants in this region are statistically more likely to be disea se-associated (Walsh 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria a pplied: ACMG/AMP criteria applied: PS4, PM2, PP3, PM1.
CSER_CC_NCGL; University of Washington Medical Center RCV000148711 SCV000190441 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000148711 SCV000207090 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-09 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223879 SCV000280360 likely pathogenic not provided 2012-08-06 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.Val320Met (c.958 G>A) in the MYH7 gene. We re-reviewed these results on 6/27/2012 and again on 10/1/13 and February 9th, 2015. Based on the strong case data and very low frequency in the general population, we consider this variant likely disease causing. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient). There is weak segregation data. Havndrup et al (2003) observed this variant in a Danish woman with HCM (likely the same case that was included in Ho et al 2009). Her 15yo daughter had a proximal 'septal bulb' and also carried the variant. Fokstuen et al (2011) observed the variant in one patient with HCM recruited from Europe (not Denmark). Santos et al (2012) reported the variant in one patient with HCM in their Portugese cohort. We have seen this variant in one other HCM patient in our cohort. She had 12 HCM genes sequenced at PGxHealth/Familion and only this variant was found. Marsiglia et al (2013) sequenced MYH7, MYBPC3, TNNT2 in 268 Brazilian patients with HCM and found the variant in 5 patients. Alvarez-Acosta et al (2014) reported the variant in 1 of 124 HCM patients recruited from a clinic in Spain. It isn't entirely clear but it looks like the patient underwent sequencing of MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL2, MYL3, TNNC1. The patient also had a variant in MYL2. He had a relatively severe phenotyped, diagnosed at 16yo, with atrial fibrillation, 2.6 cm wall thickness, syncope, left ventricular outflow tract obstruction, heart failure, LBBB, ICD, and underwent alcohol ablation. His first cousin carried only the MYL2 variant and also had HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The valine at codon 320 is completely conserved across species, though not all neighboring amino acids are. I could not find any other variants reported in association with disease at this codon, though there are a few at nearby codons (p.Phe312Cys, p.Ala326Pro). In total the variant has been seen in ~1-4/60,452 published controls, laboratory controls, and publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 10/1/13). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, variants with strong evidence for pathogenicity have been observed at similar low frequencies in this data set. The variant was reported online in 1 of 59,906 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 9th, 2015). Specifically, the variant was observed in 1 individual of African descent. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, the ESP and ExAC databases overlap (ExAC includes ESP). The discrepancy between them may be attributable to the primary data being re-analyzed in ExAC. The Seidman group observed the variant in 2 of 1963 individuals from the Jackson Heart Study who underwent sequencing of eight sarcomere genes (Bick et al 2012). They note the following about those individuals phenotypes: a 41yo with left ventricular wall thickness of 1 cm, LVDD of 4.2, LAD of 3.83, and FS of 0.38 and no known physiological risk factors; a 63yo with LVWT 1.02 cm, LVDD 4.54, LAD 3.69, FS 0.43 and no known physiological risk factors. The Jackson Heart Study is included in ExAC. The variant was not observed in the following published control samples: 100 Danish individuals (Havndrup et al 2003), 246 German and Italy individuals with normal echocardiograms and a mean age of 71 years (Fokstuen et al 2011). PGxHealth/Familion reported in another patient's report that they have not seen this variant in 200 controls of varying ancestry.

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