ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2544G>C (p.Glu848Asp) (rs730880899)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221330 SCV000208780 uncertain significance not specified 2016-10-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The E848D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has previously been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, but segregation data is absent. In addition, this variant has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000272040.1, SCV000280327.1; Landrum et al., 2016). The E848D variant 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. This substitution occurs at a position that is conserved across species and 2/3 in silico prediction programs predict this variant is probably damaging to the protein structure/function. However, the E848D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the E848D variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000221330 SCV000272040 uncertain significance not specified 2015-04-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu848Asp in MYH7 has not been previously reported in individuals with cardiomyopathy or in large population studies. The glutamate residue (Glu) at position 848 is high ly conserved in mammals and across evolutionarily distant species, and the chang e to aspartic acid (Asp) was predicted to be pathogenic using a computational to ol clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there i s some suspicion for a pathogenic role, the clinical significance of the p.Glu84 8Asp variant is uncertain.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000221330 SCV000280327 uncertain significance not specified 2014-11-29 no assertion criteria provided clinical testing 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.Glu848Asp (c.2544G>C) in MYH7 This is a conservative amino acid substitution with a hydrophilic Glutamine replaced with a hydrophilic Asparagine. Conservation analysis indicates that Glutamine is highly conserved at this position and in silico algorithms (Adzhubei et al 2010) predict the amino acid change to be probably damaging to protein structure/function. Missense variants in nearby codons (Lys847Glu, Ala850Asp, and Ala850Thr) have been reported in association with cardiomyopathy thus indicating a functional significance of this region of beta myosin heavy chain protein. In total p.Glu848Asp has not been observed in ~5500 individuals of varying ancestry. GeneDx reports the absence of the variant in 200 presumably healthy controls of both Caucasian and African American ancestry. The variant is not currently listed in NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). This dataset includes variant calls on approximately ~5300 well phenotyped individuals of Caucasian and African American descent (as of January 2012). The variant is not reported in dbSNP or 1000 Genomes (As of January 2012).

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