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

gnomAD frequency: 0.00002  dbSNP: rs376897125

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223879	SCV000208707	likely pathogenic	not provided	2024-06-30	criteria provided, single submitter	clinical testing	Not observed at 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: 23299917, 24093860, 25637381, 23197161, 22429680, 12566107, 27247418, 27532257, 22857948, 21239446, 33588347, 20031602, 33673806, 34542152, 25937619, 33764162, 29300372, 37652022, 28771489)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201440	SCV000256154	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549661	SCV000623763	pathogenic	Hypertrophic cardiomyopathy	2024-12-12	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 320 of the MYH7 protein (p.Val320Met). This variant is present in population databases (rs376897125, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12566107, 20031602, 21239446, 22857948, 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 161328). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000549661	SCV000710839	likely pathogenic	Hypertrophic cardiomyopathy	2023-02-06	criteria provided, single submitter	clinical testing	The p.Val320Met variant in MYH7 has been reported in over 20 individuals with hypertrophic cardiomyopathy (HCM; Brito 2012 PMID: 22857948, Fokstuen 2011 PMID: 21239446, Havndrup 2003 PMID: 12566107, Homburger 2016 PMID: 27247418, Jensen 2013 PMID: 23197161, Marsiglia 2013 PMID: 24093860, Walsh 2017 PMID: 27532257, LMM data) and segregated with disease in at least one affected relative from one family (Havndrup 2003 PMID: 12566107). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161328) and has also been identified in 0.0029% (2/68040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.1). Computational prediction tools and conservation analysis are consistent with pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). 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 applied: PS4, PM2_Supporting, PP3, PM1.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000201440	SCV001423552	likely pathogenic	Hypertrophic cardiomyopathy 1	2020-03-10	criteria provided, single submitter	research
Ambry Genetics	RCV002381459	SCV002694725	likely pathogenic	Cardiovascular phenotype	2024-09-12	criteria provided, single submitter	clinical testing	The p.V320M variant (also known as c.958G>A), located in coding exon 9 of the MYH7 gene, results from a G to A substitution at nucleotide position 958. The valine at codon 320 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in numerous hypertrophic cardiomyopathy cohorts (Havndrup O et al. Cardiovasc. Res., 2003 Feb;57:347-57; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Jensen MK et al. Circulation, 2013 Jan;127:48-54; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82). In addition, 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000223879	SCV003834085	likely pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531969	SCV004356962	likely pathogenic	Cardiomyopathy	2022-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 320 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least thirteen unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12566107, 21239446, 22857948, 24093860, 27532257, 28771489, 30775854, 33588347, 33764162). This variant has been identified in 4/251342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000201440	SCV005399583	likely pathogenic	Hypertrophic cardiomyopathy 1	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. ClinGen MYH7 guidelines: Likely Pathogenic: PM1 + PM2 + PS4 + PP3 Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796) (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) For this patient: autosomal dominant inheritance with digenic dominance applies (Cardiomyopathy, hypertrophic, 1. OMIM: 192600) 0112 - Variants in this gene are known to have reduced penetrance: PMID: 29300372: Kelly, MA. et al. (2018), Florescu, C. (2017) (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (0.0000159 (4 Het, 0 Hom) gnomAD v2.1.1. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 4/4 in silico analyses. Minor amino acid. High conservation. 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. (P) Hotspot region (amino acids 181-937) (PMID: 29300372). 0708 Comparable variants have conflicting previous evidence for pathogenicity. (N) p.(Val320Glu), major amino acid change: Likely pathogenic in ClinVar x1. LOVD3: 2x Likely pathogenic + 2x VUS by VKGL data sharing initiative. 0801 Strong previous evidence of pathogenicity in unrelated individuals. (P) >15 unrelated probands with this variant. ClinVar: Conflicting interpretations of pathogenicity: 7 submissions: 5x Likely Pathogenic + 2x VUS. Publications: PMID: 12566107 (and follow-up PMID: 23197161). PMID: 21239446. PMID: 22857948. PMID: 24093860. Álvarez-Acosta, L. et al. (2014). PMID: 27247418. PMID: 27532257. 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
All of Us Research Program, National Institutes of Health	RCV000549661	SCV005431159	likely pathogenic	Hypertrophic cardiomyopathy	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 320 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least thirteen unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12566107, 21239446, 22857948, 24093860, 27532257, 28771489, 30775854, 33588347, 33764162). This variant has been identified in 4/251342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003491	SCV005629713	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2024-06-17	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	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.