Submissions for variant NM_000257.4(MYH7):c.1048T>C (p.Tyr350His)

dbSNP: rs730880863

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158780	SCV000208715	pathogenic	not provided	2013-10-31	criteria provided, single submitter	clinical testing	p.Tyr350His (TAT>CAT): c.1048 T>C in exon 12 of the MYH7 gene (NM_000257.2). While the Tyr350His mutation in the MYH7 gene has not been reported to our knowledge, a mutation affecting this same residue, Tyr350Asn, has been reported as a de novo mutation in association with Ebstein anomaly and biventricular noncompaction (Postma A et al., 2011). Additionally, mutations in nearby residues (Met349Thr, Lys351Glu, Ala355Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this residue and this region of the protein. Tyr350His results in a semi-conservative amino acid substitution of neutral, polar Tyrosine with a positively charged Histidine at a position that is conserved across species. In silico analysis predicts Tyr350His is damaging to the protein structure/function. Furthermore, Tyr350His 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. In summary, Tyr350His in the MYH7 gene is interpreted as a likely disease-causing mutation. The variant is found in DCM-CRDM panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192690	SCV001360971	uncertain significance	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1048T>C (p.Tyr350His) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1048T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.