ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.1705G>A (p.Asp569Asn) (rs200641225)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438420 SCV000514180 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEKHG5 gene. The D569N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D569N variant is observed in 82/126484 (0.06%) alleles from individuals of European background (Lek et al., 2016). The D569N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000525392 SCV000646007 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 569 of the PLEKHG5 protein (p.Asp569Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200641225, ExAC 0.06%). This variant has been reported in an individual affected with inherited peripheral neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 378377). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.

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