ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs144066768
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Total submissions: 5
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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.
Invitae 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.

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