ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5507C>T (p.Ser1836Leu) (rs727503242)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000151235 SCV000513812 uncertain significance not specified 2016-05-12 criteria provided, single submitter clinical testing An S1836L variant of uncertain significance was identified in the MYH7 gene. S1836L has been reported in an individual with childhood-onset cardiac hypertrophy and a family history of cardiomyopathy (Morita et al., 2008); however, no family or functional studies have been reported to our knowledge. In the same study, S1836L was not observed in 180 unrelated, ancestrally matched persons and more than 1000 chromosomes of unaffected persons. Similarly, the S1836L variant 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. The S1836L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000459205 SCV000546178 uncertain significance Hypertrophic cardiomyopathy 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1836 of the MYH7 protein (p.Ser1836Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs727503242, ExAC 0.01%). This variant has been reported in individuals affected with dilated cardiomyopathy and childhood-onset cardiac hypertrophy (PMID: 29540472 18403758). ClinVar contains an entry for this variant (Variation ID: 164268). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000786172 SCV001149159 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001115176 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 Clinical Services Laboratory,Illumina RCV001115177 SCV001273134 benign Myopathy, distal, 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). 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 Clinical Services Laboratory,Illumina RCV001115178 SCV001273135 uncertain significance Familial 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 RCV001177616 SCV001341856 uncertain significance Cardiomyopathy 2020-02-25 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000151235 SCV000280368 uncertain significance not specified 2012-10-02 no assertion criteria provided 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

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