Submissions for variant NM_002471.4(MYH6):c.3598G>C (p.Asp1200His)

gnomAD frequency: 0.00019  dbSNP: rs372794975

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473507	SCV000546154	uncertain significance	Hypertrophic cardiomyopathy 14	2023-05-19	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs372794975, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1200 of the MYH6 protein (p.Asp1200His). 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 MYH6 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 407151). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607798	SCV000711402	uncertain significance	not specified	2017-05-18	criteria provided, single submitter	clinical testing	The p.Asp1200His variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (14/23478) of African chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org/; dbSNP rs372794975). This variant has been reported in ClinVar (Variation ID: 407151) as of uncertain significance. Computational prediction tools and co nservation analysis suggest that the p.Asp1200His variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.Asp1200His variant is uncertain.
GeneDx	RCV001595007	SCV001829319	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	Reported in a pediatric patient with dilated cardiomyopathy; additional clinical data were not described (Burstein et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32746448)
Ambry Genetics	RCV002451098	SCV002614914	uncertain significance	Cardiovascular phenotype	2023-08-01	criteria provided, single submitter	clinical testing	The p.D1200H variant (also known as c.3598G>C), located in coding exon 24 of the MYH6 gene, results from a G to C substitution at nucleotide position 3598. The aspartic acid at codon 1200 is replaced by histidine, an amino acid with similar properties. This variant has been detected in a pediatric dilated cardiomyopathy case and in a pediatric restrictive cardiomyopathy case; however, detail was limited (Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476; Ware SM et al. Am J Hum Genet. 2022 Feb;109(2):282-298). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002489034	SCV002778356	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-07-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001595007	SCV004236698	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001595007	SCV001918357	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001595007	SCV001969541	uncertain significance	not provided		no assertion criteria provided	clinical testing