ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.226G>A (p.Gly76Arg) (rs368413008)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507992 SCV000604393 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing The p.Gly76Arg variant (rs368413008) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.01 percent (identified on 1 out of 13006 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.004 percent (identified on 5 out of 120192 chromosomes). The glycine at position 76 is weakly conserved (considering 12 species, Alamut v.2.9.0) but computational analyses of the effects of the p.Gly76Arg variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Gly76Arg variant with certainty.
Ambry Genetics RCV000618160 SCV000739311 uncertain significance Cardiovascular phenotype 2016-10-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000548227 SCV000650523 uncertain significance Aortic aneurysm, familial thoracic 7 2017-09-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 76 of the MYLK protein (p.Gly76Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs368413008, ExAC 0.01%) but has not been reported in the literature in individuals with a MYLK-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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