Submissions for variant NM_000257.4(MYH7):c.5507C>T (p.Ser1836Leu)

gnomAD frequency: 0.00004  dbSNP: rs727503242

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151235	SCV000199103	uncertain significance	not specified	2014-04-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000786172	SCV000513812	uncertain significance	not provided	2019-09-13	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 164268; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18403758, 29540472, 32880476)
Invitae	RCV000459205	SCV000546178	uncertain significance	Hypertrophic cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1836 of the MYH7 protein (p.Ser1836Leu). This variant is present in population databases (rs727503242, gnomAD 0.03%). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 18403758, 29540472, 34495297). ClinVar contains an entry for this variant (Variation ID: 164268). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 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.
Illumina Laboratory Services, Illumina	RCV003320106	SCV001273133	uncertain significance	Myosin storage myopathy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001115177	SCV001273134	benign	MYH7-related skeletal myopathy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001115178	SCV001273135	uncertain significance	Hypertrophic cardiomyopathy 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001177616	SCV001341856	uncertain significance	Cardiomyopathy	2023-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1836 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 33495596). This variant has been identified in 20/281784 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.
Ambry Genetics	RCV002345470	SCV002652844	uncertain significance	Cardiovascular phenotype	2021-04-09	criteria provided, single submitter	clinical testing	The p.S1836L variant (also known as c.5507C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5507. The serine at codon 1836 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in one case from a hypertrophic cardiomyopathy (HCM) cohort and another case from a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited in both cases (Morita H et al. N. Engl. J. Med., 2008 May;358:1899-908; Hazebroek MR et al. Circ Heart Fail, 2018 Mar;11:e004682). This alteration has also been reported in the Jackson Heart study population-based longitudinal study (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177616	SCV004239485	uncertain significance	Cardiomyopathy	2023-04-03	criteria provided, single submitter	clinical testing
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003514312	SCV004363573	uncertain significance	Dilated cardiomyopathy 1S	2023-11-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001177616	SCV004814348	uncertain significance	Cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1836 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 33495596). This variant has been identified in 20/281784 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000151235	SCV000280368	uncertain significance	not specified	2012-10-02	flagged submission	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. In silico analysis with HCM PolyPhen-2 predicts the variant to be pathogenic. The Ser at codon 1836 is conserved across mammalian species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (1829, 1832, 1846). In total the variant has not been seen in published controls and individuals from publicly available population datasets. There is no variation at codon 1836 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of April 8, 2015). Note that this dataset does not match the patient's ancestry (Indian). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of April 8, 2015). There is variation at codon 1836 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 8, 2015). Eight individuals have missense variants at codon 1836 (six with S1836L and two with S1836W). Two individuals synonymous variation at that position. The Framingham cohort was included in EXAC, so it's likely that one of those six missense cases was likely from the individual above. There also happens to be missense variation (and one frameshift variant) at every codon from 1832-1836.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786172	SCV000924878	uncertain significance	not provided	2015-04-08	no assertion criteria provided	provider interpretation