ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.638C>T (p.Ala213Val) (rs367543633)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235831 SCV000292665 uncertain significance not provided 2016-05-05 criteria provided, single submitter clinical testing The A213V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A213V variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Several in-silico splice prediction models predict that c.638C>T creates a cryptic donor site upstream of the natural donor site in exon 8 which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.638C>T variant does not effect splicing, it will result in a A213V missense variant. The A213V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and Valine is seen in more distanly related species. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000532897 SCV000646059 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 213 of the PLEKHG5 protein (p.Ala213Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. While this variant is present in population databases (rs367543633), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 245661). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, this variant has uncertain impact on PLEKHG5 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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