Submissions for variant NM_006017.3(PROM1):c.2094C>A (p.Ser698Arg)

dbSNP: rs199727800

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001146428	SCV001307171	likely benign	Stargardt disease 4	2017-09-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001146429	SCV001307172	uncertain significance	Retinal macular dystrophy type 2	2017-09-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146430	SCV001307173	uncertain significance	Retinitis pigmentosa	2017-09-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001149203	SCV001310141	benign	Cone-rod dystrophy 12	2017-09-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229010	SCV001401441	uncertain significance	not provided	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 698 of the PROM1 protein (p.Ser698Arg). This variant is present in population databases (rs199727800, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PROM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 900895). 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 not expected to disrupt PROM1 protein function with a negative predictive value of 80%. 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.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004813801	SCV005069496	uncertain significance	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734032	SCV005360182	uncertain significance	PROM1-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The PROM1 c.2094C>A variant is predicted to result in the amino acid substitution p.Ser698Arg. This variant was reported in a heterozygous state in individual with Leber congenital amaurosis (Eisenberger et al 2013. PubMed ID: 24265693); however, this individual was also apparently homozygous for a frameshift variant in RPGRP1. This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.