ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2536G>C (p.Glu846Gln)

gnomAD frequency: 0.00001  dbSNP: rs730880748
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172050 SCV000051006 uncertain significance Hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
GeneDx RCV000158546 SCV000208481 pathogenic not provided 2013-02-13 criteria provided, single submitter clinical testing p.Glu846Gln (GAG>CAG): c.2536 G>C in exon 22 of the MYH7 gene (NM_000257.2). The Glu846Gln mutation in the MYH7 gene has been reported in association with HCM (Havndrup O et al., 2003; Ho C et al., 2009). Havndrup et al. identified Glu846Gln in one family with three affected individuals who harbored this mutation and it was not observed in 100 control individuals. Other asymptomatic carriers of this mutation were found in younger generations, which the authors suggested was due to reduced penetrance in this family. Mutations in this codon (Glu846Lys) and in nearby codons (Glu844Lys, Arg845Gly, Lys847Glu, Met849Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, Glu846Gln 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. In summary, Glu846Gln in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Ambry Genetics RCV000253031 SCV000319790 likely pathogenic Cardiovascular phenotype 2022-01-31 criteria provided, single submitter clinical testing The p.E846Q variant (also known as c.2536G>C), located in coding exon 20 of the MYH7 gene, results from a G to C substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by glutamine, 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 alteration has been detected in several individuals with hypertrophic cardiomyopathy (HCM) and was reported to segregate with disease in one family (Havndrup O et al. Cardiovasc Res. 2003;57:347–357; Ho CY et al. Circ Cardiovasc Genet. 2009;2:314-321; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170274 SCV001332837 likely pathogenic Cardiomyopathy 2022-04-13 criteria provided, single submitter clinical testing
Invitae RCV000172050 SCV001486522 pathogenic Hypertrophic cardiomyopathy 2023-11-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 846 of the MYH7 protein (p.Glu846Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 12566107, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181194). 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%. 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.
Color Diagnostics, LLC DBA Color Health RCV001170274 SCV004356916 likely pathogenic Cardiomyopathy 2022-08-04 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glutamine at codon 846 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 at least 7 individuals affected with hypertrophic cardiomyopathy (PMID: PMID: 12566107, 19035361, 20031602, 27532257, communication with external laboratories: ClinVar SCV001486522.2 and SCV000319790.5). It has been shown that this variant segregates with hypertrophic cardiomyopathy in three individuals from one of the families (PMID: 12566107, 19035361). 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.

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