Submissions for variant NM_000257.4(MYH7):c.5203T>A (p.Ser1735Thr)

gnomAD frequency: 0.00001  dbSNP: rs144066768

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158685	SCV000208620	uncertain significance	not provided	2016-09-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The S1735T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported previously in one other individual referred for HCM genetic testing at GeneDx. The S1735T variant was not observed with any significant frequency 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. Nevertheless, the S1735T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819479	SCV000960143	uncertain significance	Hypertrophic cardiomyopathy	2023-05-23	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181272). This missense change has been observed in individual(s) with Brugada syndrome and/or hypertrophic cardiomyopathy (PMID: 26220970, 33297573). This variant is present in population databases (rs144066768, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1735 of the MYH7 protein (p.Ser1735Thr).
Color Diagnostics, LLC DBA Color Health	RCV001176077	SCV001339915	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1735 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33297573) as well as in a healthy individual (PMID: 31983221). This variant has also been identified in 5/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002484980	SCV002777178	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362699	SCV004080747	uncertain significance	Cardiovascular phenotype	2023-08-21	criteria provided, single submitter	clinical testing	The p.S1735T variant (also known as c.5203T>A), located in coding exon 34 of the MYH7 gene, results from a T to A substitution at nucleotide position 5203. The serine at codon 1735 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort; however, details were limited and this variant has also been detected in individuals from control cohorts without know cardiomyopathy (Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001176077	SCV004814359	uncertain significance	Cardiomyopathy	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1735 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33297573) as well as in a healthy individual (PMID: 31983221). This variant has also been identified in 5/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.