ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with ebstein anomaly and mild hypertrabeculation of the apex, but also identified in her father with normal echo; ClinVar: VUS for first degree atrioventricular block

Variant summary: MYH7 c.4717G>A (p.Glu1573Lys) results in a conservative amino acid change in the encoded protein sequence within the Myosin tail (IPR002928). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251370 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.4717G>A has been reported in the literature in individuals affected with Cardiomyopathy, Left ventricular hypertrabeculation, and Ebstein's anomaly (Jamka_2017, Verdonschot_2020, Postma_2011, Haas_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with another pathogenic variant has been reported (MYH7 c.2167C>T, p.Arg723Gly, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in an individual affected with cardiac defects and in an unaffected relative, as well as in an individual with left ventricular noncompation in the published literature (Postma et al., 2011; Miszalski-Jamka et al., 2017); Reported in a patient with HCM referred for genetic testing at GeneDx who harbored an additional pathogenic variant that may explain their phenotype; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222729; ClinVar); This variant is associated with the following publications: (PMID: 21127202, 32880476, 28798025, 34542152, Vepslinen2022[CaseReport])

The MYH7 c.4717G>A variant is predicted to result in the amino acid substitution p.Glu1573Lys. This variant was reported in individuals with Ebstein anomaly, left ventricular noncompaction, or dilated cardiomyopathy (Postma et al. 2011. PubMed ID: 21127202; Table S6, Haas et al. 2014. PubMed ID: 25163546; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). However, this variant was also documented in unaffected family members or control individuals (Postma et al. 2011. PubMed ID: 21127202; Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23885449-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces glutamic acid with lysine at codon 1573 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 an individual affected with left ventricular non-compaction (PMID: 28798025) and in an individual with dilated cardiomyopathy (PMID: 32880476). This variant has also been reported in an individual affected with Ebstein anomaly and perimembranous ventricular septal defect, as well as in the unaffected father (PMID: 21127202). This variant has been identified in 15/251370 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.

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. 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. ClinVar contains an entry for this variant (Variation ID: 222729). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 21127202, 28798025, 32880476). This variant is present in population databases (rs750987717, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1573 of the MYH7 protein (p.Glu1573Lys).

This missense variant replaces glutamic acid with lysine at codon 1573 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 an individual affected with left ventricular non-compaction (PMID: 28798025) and in an individual with dilated cardiomyopathy (PMID: 32880476). This variant has also been reported in an individual affected with Ebstein anomaly and perimembranous ventricular septal defect, as well as in the unaffected father (PMID: 21127202). This variant has been identified in 15/251370 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.

The p.E1573K variant (also known as c.4717G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4717. The glutamic acid at codon 1573 is replaced by lysine, an amino acid with similar properties. This variant was detected in a proband with Ebstein's anomaly, mild apical hypertrabeculation and VSD, but was also detected in an unaffected parent (Postma AV et al. Circ Cardiovasc Genet, 2011 Feb;4:43-50). This variant has also been detected in a case reported to have left ventricular non-compaction, a case with dilated cardiomyopathy, and in a hypertrophic cardiomyopathy cohort; however, details were limited and additional variants in cardiac-related genes were also detected in some cases (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This variant has also been detected in three individuals from an exome sequencing cohort who were not known to have cardiomyopathy or skeletal myopathy (Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). 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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated part of skip three of the light meromyosin region (PMID: 26150528). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS and has been observed in individuals with hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, and dilated cardiomyopathy (ClinVar, PMID: 30847666, PMID: 28798025, PMID: 21127202, VCGS). This variant has also been reported in an Ebstein anomaly proband and her unaffected father (PMID: 21127202). Additionally, this variant was identified in a HCM proband referred for genetic testing at GeneDx who had an additional pathogenic variant that may explain their phenotype (ClinVar). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign