ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3286G>T (p.Asp1096Tyr) (rs45478699)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201875 SCV000256636 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-30 criteria provided, single submitter research The Asp1096Tyr variant in MYH7 has been previously reported by Hershberger et al (2008) in 2 DCM probands. Helms et al (2014) analysed sarcomere transcript and protein levels in septal myectomy and transplant specimens from genotyped HCM patients - one of whome carried this MYH Asp1096Tyr variant. This variant has been reported with an allele frequency of 0.0001 (18/66,720 European non-Finnish alleles and 1/908 'other') in the Exome Aggregation Consortium dataset ( The MYH7 Asp1096Tyr variant occurs in a conserved region, and in-silico tools (SIFT, PolyPhen, MutationTaster and CADD) support a damaging role for this variant, however this alone is not strong evidence for pathogenicity. We have identified this variant in 1 HCM proband who presented in her 30's with asymmetric hypertrophy (IVS 21mm) and obstruction. This proband experienced a sudden cardiac death in her 50s. It is noted that this proband also carried a pathogenic MYBPC3 nonsense variant. Based on the limited reports in the literature, and our finding of MYH7 Asp1096Tyr in an isolated HCM case who carried an additional variant which is known to be disease-causing, we have classified this variant as having "uncertain significance". Additional evidence is required to fully establish its pathogenic role.
Ambry Genetics RCV000620264 SCV000736672 uncertain significance Cardiovascular phenotype 2016-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000590886 SCV000700123 likely pathogenic Dilated cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758039 SCV000577981 uncertain significance Cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been reported in 4 individuals with hypertrophic cardiomyopathy (PMID:25031304; PMID:27532257; SHaRe; AGCMC Sydney ClinVar SCV000256636.2) but has also been identified in 0.027% (18/66720) of European chromosomes by ExAC ( Since the MYH7 specifications state that PS4 is only applicable if variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3
Color RCV000758039 SCV000913719 uncertain significance Cardiomyopathy 2018-06-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the neck and hinge region (S2 domain) of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. While this variant has been reported in individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304), it has also been identified in 38/277202 chromosomes (37/126692 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491282 SCV000298099 uncertain significance Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided clinical testing
GeneDx RCV000656921 SCV000208535 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing The D1096Y variant of uncertain significance in the MYBPC3 gene has been reported in association with both HCM (Helms et al., 2014; Helms et al., 2016) and DCM (Hershberger et al., 2008; Haas et al., 2015; Hazebroek et al., 2015). This variant has also been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. No informative segregation data are available to our knowledge. The D1096Y variant is observed in 37/126692 (0.029%) alleles in individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The D1096Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, expression analysis in septal myectomy tissue from an HCM patient harboring D1096Y showed the variant and wild-type transcripts, as well as proteins, are expressed at approximately the expected 1:1 ratio for a heterozygous individual (Helms et al., 2014). Furthermore, no studies have been performed to determine the functional effect of the D1096Y variant to our knowledge. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000529912 SCV000623693 uncertain significance Hypertrophic cardiomyopathy 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein (p.Asp1096Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs45478699, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 29300372, 25163446) and left ventricular noncompaction (LVNC) (PMID: 28798025). ClinVar contains an entry for this variant (Variation ID: 42953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035846 SCV000059497 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1096Ty r variant has been previously reported in 3 individuals with DCM and 1 teenager with left ventricular hypertrophy and a family history of DCM (Hershberger 2008, Helms 2014, LMM data). This variant has also been identified in 18/66702 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti; dbSNP rs45478699). Aspartic acid (Asp) at position 1096 is highly cons erved in mammals and the change to tyrosine (Tyr) was predicted to be pathogenic using a computational tool 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 is some suspicion for a pathogenic role, the clinical si gnificance of the p.Asp1096Tyr variant is uncertain.

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