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

dbSNP: rs730880746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721009	SCV000208478	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 27532257, 29300372)
Laboratory for Molecular Medicine, Mass General Brigham 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	pathogenic	Hypertrophic cardiomyopathy	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 833 of the MYH7 protein (p.Tyr833His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27247418, 31983222; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Y883H. ClinVar contains an entry for this variant (Variation ID: 181192). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002426778	SCV002740916	uncertain significance	Cardiovascular phenotype	2017-12-22	criteria provided, single submitter	clinical testing	The p.Y833H variant (also known as c.2497T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide position 2497. The tyrosine at codon 833 is replaced by histidine, an amino acid with similar properties. This alteration was reported in one individual from a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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).