Submissions for variant NM_000539.3(RHO):c.512C>A (p.Pro171Gln)

dbSNP: rs2084776162

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074404	SCV001239985	pathogenic	Retinal dystrophy	2019-08-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090663	SCV001246336	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001265188	SCV001443221	pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001090663	SCV001580420	pathogenic	not provided	2023-06-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro171 amino acid residue in RHO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1833777, 8253795, 29847639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RHO function (PMID: 30977563). 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 RHO protein function. ClinVar contains an entry for this variant (Variation ID: 866418). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 7987326, 11139241; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 171 of the RHO protein (p.Pro171Gln).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001724238	SCV001950345	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Pro171Gln variant in RHO was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001265188	SCV005398216	pathogenic	Retinitis pigmentosa 4	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with RHO-related conditions. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with dominant conditions in this gene are known to have variable expressivity and age of onset (PMID: 26887858). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated 7 transmembrane receptor (rhodopsin family) domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Pro171Arg), p.(Pro171Leu) and p.(Pro171Ser) have been classified as pathogenic by clinical laboratories in ClinVar, and the latter has also been observed in a family with autosomal dominant retinitis pigmentosa in the literature (PMID: 11139241). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar, and has been observed in several individuals with autosomal dominant retinitis pigmentosa in the literature (PMIDs: 11139241, 29099798, 7987326). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign