Submissions for variant NM_000322.5(PRPH2):c.518A>C (p.Asp173Ala)

dbSNP: rs61755794

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379736	SCV001577585	pathogenic	PRPH2-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 173 of the PRPH2 protein (p.Asp173Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant inherited retinal dystrophy (PMID: 31456290; Invitae). ClinVar contains an entry for this variant (Variation ID: 812387). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRPH2 protein function. This variant disrupts the p.Asp173 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been observed in individuals with PRPH2-related conditions (PMID: 8019570), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV002250712	SCV002521123	likely pathogenic	Retinitis pigmentosa 7	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is shared with similarly affected family member (EPL21-UNBO). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 31456290). Different missense changes at the same codon (p.Asp173Gly, p.Asp173Val) have been reported to be associated with PRPH2 related disorder (ClinVar ID: VCV000013181, VCV000866675 / PMID: 8019570). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003146	SCV001161215	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Leiden Open Variation Database	RCV001530227	SCV001744964	likely pathogenic	not provided	2020-08-28	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Global Variome, with Curator vacancy.