ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.946A>G (p.Met316Val) (rs201672777)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586009 SCV000698454 uncertain significance not provided 2016-03-29 criteria provided, single submitter clinical testing Variant summary: This c.946A>G variant affects a conserved nucleotide, resulting in amino acid change from Met to Val. 3/4 in-silico tools predict this variant to be damaging. This variant was found in 3/120762 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0000248, which is 2.48 times greater than the maximal expected frequency of a pathogenic allele (0.00001) in this gene, suggesting this variant is benign. However, only three variant occurrences may not provide a believable comparison. In addition, it is may not be likely that all individuals from ExAC were cardiographically evaluated to be normal, thus the populations may or may not represent a true control population for silent diseases like ARYTH. This variant was found in one child with sudden death by drowning who also carried other three variants of unknown significance. Taken together this variant has currently been classified as a Variant of Uncertain Significance.
Invitae RCV000795477 SCV000934941 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 316 of the DSP protein (p.Met316Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs201672777, ExAC 0.005%). This variant has been observed in an individual affected with sudden cardiac death (PMID: 25447171). ClinVar contains an entry for this variant (Variation ID: 496252). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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