PP2

This sequence change in MYH7 is predicted to replace glutamic acid with aspartic acid at codon 800, p.(Glu800Asp). The Glu800 residue is highly conserved (100 vertebrates, Multiz Alignments), and is located between myosin head and myosin tail domains, which falls within a region (amino acids 167-931) defined as a mutational hotspot. There is a small physicochemical difference between glutamic acid and aspartic acid. The highest population minor allele frequency in the population database v4.1 is 0.0006% (7/1,180,038 alleles) in the non-Finnish European population. This variant has been reported in at least two probands with hypertrophic cardiomyopathy (PMID: 30847666; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2_Supporting, PP3, PS4_Supporting.

This missense variant replaces glutamic acid with aspartic acid at codon 800 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 800 of the MYH7 protein (p.Glu800Asp). This variant is present in population databases (rs730880737, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181183). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The MYH7 p.Glu800Asp variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs730880737) and in control databases in 1 of 251474 chromosomes at a frequency of 0.000003977 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 1 of 113752 chromosomes (freq: 0.000009), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Glu800 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.