ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5088G>C (p.Glu1696Asp)

gnomAD frequency: 0.00003  dbSNP: rs373219734
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000213375 SCV000272054 uncertain significance not specified 2015-08-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1696As p variant in MYH7 has not been previously reported in individuals with cardiomyo pathy, but has been identified in 3/66728 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373219734). Th is variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to b e correct 94% of the time (Jordan 2011). In summary, while there is some suspic ion for a pathogenic role, the clinical significance of the p.Glu1696Asp variant is uncertain.
Invitae RCV000628860 SCV000749768 uncertain significance Hypertrophic cardiomyopathy 2023-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1696 of the MYH7 protein (p.Glu1696Asp). This variant is present in population databases (rs373219734, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 228914). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.
Color Diagnostics, LLC DBA Color Health RCV001523969 SCV001733715 uncertain significance Cardiomyopathy 2023-07-27 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 1696 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495597). This variant has been identified in 8/251304 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.
Ambry Genetics RCV002517567 SCV003707828 uncertain significance Inborn genetic diseases 2022-08-08 criteria provided, single submitter clinical testing The c.5088G>C (p.E1696D) alteration is located in exon 35 (coding exon 33) of the MYH7 gene. This alteration results from a G to C substitution at nucleotide position 5088, causing the glutamic acid (E) at amino acid position 1696 to be replaced by an aspartic acid (D). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (8/251304) total alleles studied. The highest observed frequency was 0.006% (7/113616) of European (non-Finnish) alleles. This alteration has been reported in patients with hypertrophic cardiomyopathy by two independent studies looking at susceptibility loci for cardiomyopathies (Walsh, 2017; Harper, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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