ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2497T>C (p.Tyr833His) (rs730880746)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158543 SCV000208478 uncertain significance not specified 2012-08-31 criteria provided, single submitter clinical testing The Tyr833His variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Tyr833His results in a non-conservative amino acid substitution of neutral, polar Tyrosine with a positively charged Histidine at a position that is not uniformly conserved across species. However, mutations in nearby residues (Val824Ile, Trp827Cys, Pro828Ser, Lys835Thr, Pro838Leu) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. In addition, the NHLBI ESP Exome Variant Server reports Tyr833His was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The clinical significance of Tyr833His in the MYH7 gene remains unknown. The variant is found in HCM panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000158543 SCV000272037 uncertain significance not specified 2016-01-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr833His variant in MYH7 has not been previously reported in individuals with cardiomyop athy or in large population studies. This variant 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.Tyr833His variant is uncertain.
Invitae RCV000814855 SCV000955287 uncertain significance Hypertrophic cardiomyopathy 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 833 of the MYH7 protein (p.Tyr833His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family and has been reported in an individual affected with this disease (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181192). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158543 SCV000280324 uncertain significance not specified 2014-01-02 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.Tyr833His (c.2497T>C) in the MYH7 gene. This variant is novel; it has not been previously reported in association with HCM. This is a non-conservative amino acid change with a neutral Tyrosine replaced with a positively charged Histidine. Tyrosine is not uniformly conserved across species. Variants in nearby codons (p.Trp827Cys, p.Lys835Thr) have been reported in association with HCM. PolyPhen-2 predicts the variant to be probably damaging. GeneDx did not report internal control data, p.Tyr833His is not listed in dbSNP, or 1000 Genomes. Also, there is no variation at codon 833 currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6300 Caucasian and African American individuals (as of October 2nd 2012).

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