ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5528C>T (p.Ser1843Leu) (rs148621523)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417391 SCV000234825 likely benign not specified 2016-03-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000182480 SCV000319818 uncertain significance Cardiovascular phenotype 2016-09-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027836 SCV001190456 uncertain significance Aortic aneurysm, familial thoracic 4 2019-04-30 criteria provided, single submitter clinical testing MYH11 NM_002474.2 exon 39 p.Ser1843Leu (c.5528C>T): This variant has not been reported in the literature and is present in 0.06% (17/24968) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15809106-G-A). This variant is present in ClinVar (Variation ID:201039). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV001027836 SCV001274133 uncertain significance Aortic aneurysm, familial thoracic 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001116103 SCV001274134 uncertain significance Lissencephaly 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV001185497 SCV001351722 likely benign Familial thoracic aortic aneurysm and aortic dissection 2020-01-06 criteria provided, single submitter clinical testing
Invitae RCV001027836 SCV001412851 uncertain significance Aortic aneurysm, familial thoracic 4 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1850 of the MYH11 protein (p.Ser1850Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs148621523, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 201039). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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