ClinVar Genomic variation as it relates to human health

The c.619A>C (p.Lys207Gln) variant in the MYH7 gene has been identified in at least five individuals with Hypertrophic Cardiomyopathy (HCM) (PMID: 24793961, 27247418, 27532257, 25611685, 32894683). This variant has also been reported in homozygous status in a patient diagnosed at 47 years old with HCM that later seemed to transition to dilated cardiomyopathy at 64 years old. His sibling (80 years old) who is heterozygous for this variant was also diagnosed with HCM, while his three children (age range 40-46 years old) and three grandchildren (age range 3-15 years old) who were heterozygous for this variant were asymptomatic. Five of these heterozygous individuals have a resting sinus bradycardia, suggesting an alternative phenotypic expression (PMID: 12820698, 15528230). This variant is located in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations, and missense variants in this region are statistically more likely to be disease-associated (PMID:27532257). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.801). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 177674). Therefore, the c.619A>C (p.Lys207Gln) variant in the MYH7 gene is classified as likely pathogenic.

Variant summary: MYH7 c.619A>C (p.Lys207Gln) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) and is found in a surface loop that spans the entrance to the ATP-binding pocket (Alpert 2005). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246666 control chromosomes (gnomAD and publication data). c.619A>C has been reported in the literature in a family with a homozygous individual affected with Hypertrophic Cardiomyopathy (HCM) that later seemed to transition into Dilated Cardiomyopathy (DCM); although the variant was found in several family members in heterozygosity, only one of them was affected by HCM (Mohiddin 2003, Alpert 2005). The variant was also reported to be found in HCM patient cohorts in heterozygous state (Bos 2014, Homburger 2016, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, characterizing skeletal muscle myosin from biceps muscles of the homozygous patient, however, this study does not allow convincing conclusions about the variant effect (Alpert 2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The variant has been reported in association with HCM in one large family with a proband homozygous for the variant. The variant segregated with HCM in one family member (PMID: 12820698;15528230); Identified in the heterozygous state in other unrelated individuals with diagnosis of HCM in the published literature (PMID: 27532257; 27247418) and independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy at GeneDx, but segregation data is limited or absent at this time.; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18391120, 21310275, 27247418, 28420666, 20298698, 12820698, 15528230, 27532257, 29300372, 32894683, 18761664)

proposed classification - variant undergoing re-assessment, contact laboratory

This missense variant replaces lysine with glutamine at codon 207 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 24793961, 27247418, 27532257), including one individual in homozygous state with the disease onset at 47 years old. 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). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the MYH7 protein (p.Lys207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in the heterozygous and homozygous state in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 27247418, 27532257, 32894683; Invitae). ClinVar contains an entry for this variant (Variation ID: 177674). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.K207Q variant (also known as c.619A>C), located in coding exon 5 of the MYH7 gene, results from an A to C substitution at nucleotide position 619. The lysine at codon 207 is replaced by glutamine, an amino acid with similar properties. This alteration was reported in the homozygous state in an individual with apical hypertrophic cardiomyopathy (HCM), and in the heterozygous state in multiple family members, only one of whom also had HCM (Mohiddin SA et al. Genet. Test., 2003;7:21-7; Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol., 2005 Mar;288:H1097-102). This alteration has also been reported in other HCM cohorts, though clinical details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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 well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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.Lys207Gln (c.619 A>C) in MYH7 (NM_000257.2) We have seen this in a patient with early onset HCM, severe LVH, who also carries p.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) (phase not known). As reviewed below, we classify both of these variants as variants of uncertain significance, probably disease causing. They are good candidates, either individually or in combination, for the cause of his cardiomyopathy, however we cannot currently conclude with sufficient confidence that they are in fact the causative variants. The variant has been seen in at least two unrelated cases of HCM (not including this patient's family). Mohiddin et al (2003) reported a patient with HCM who was homozygous for this variant. The patient was from an NIH cohort of 100 HCM patients who had analysis of just MYH7. HCM was diagnosed at 47 years of age and at 64yo the maximal wall thickness was 2.1 cm, at the apex. History included syncope, appropriate shocks from his ICD, chronic atrial fibrillation, eventual left ventricular dilatation and heart failure class III symptoms. A sibling was a heterozygote and got diagnosed with HCM at 80yo with a thickness of 3.5 cm. Three children in their 40s were heterozygotes and had normal echos. Three grandchildren <16 yo Were also heterozygotes and had normal echos. Several heterozygotes had resting sinus bradycardia. Ancestry was not reported. Consanguinity was denied and haplotype analysis was not reported. The same case was included in a later publication by this group (Alpert et al 2005). Dr. Ackerman's group reported the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo. We have not seen this variant before. It is not currently listed in ClinVar (as of July 3rd, 2014). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.551). The lysine at codon 207 is conserved across all mammalian cardiac myosins, regardless of isoform (Alper et al 2002). Other variants have been reported in association with disease at nearby codons (Ala199Val, Ala200Thr, Ile201Thr, Arg204His, Ser205Cys, Q209E, Pro211Leu, Gly214Asp, Leu216Val per GeneDx report, referencing HGMD). In total the variant has not been seen in 6800 published controls and individuals from publicly available population datasets. There is no variation at codon 207 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). There is also no variation at this codon listed in dbSNP (as of July 3rd, 2014). The variant was not observed in the following published control samples: 100 (Mohiddin et al 2003), 200 (Bos et al 2014).