Submissions for variant NM_006245.4(PPP2R5D):c.621G>C (p.Trp207Cys)

dbSNP: rs2150278805

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV001808894	SCV002059135	likely pathogenic	Hogue-Janssens syndrome 1	2022-01-03	criteria provided, single submitter	clinical testing	A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280435, PMID:24896178, PM5_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.778, 3CNET: 0.978, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003698871	SCV004465996	pathogenic	not provided	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 207 of the PPP2R5D protein (p.Trp207Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PPP2R5D-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1333678). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Trp207 amino acid residue in PPP2R5D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24896178, 26168268). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.