Submissions for variant NM_006017.3(PROM1):c.1345G>A (p.Val449Met)

gnomAD frequency: 0.00152  dbSNP: rs200620291

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724359	SCV000225635	uncertain significance	not provided	2014-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724359	SCV000536401	uncertain significance	not provided	2017-01-24	criteria provided, single submitter	clinical testing	The V449M variant in the PROM1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports V449M was observed in 12/8500 (0.14%) alleles from individuals of Eastern European background, indicating it may be a rare variant in this population. The V449M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.We interpret V449M as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000724359	SCV000892350	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	PROM1: BP4, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724359	SCV001197758	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147666	SCV001308503	benign	Cone-rod dystrophy 12	2017-04-27	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.
Illumina Laboratory Services, Illumina	RCV001147667	SCV001308504	uncertain significance	Retinitis pigmentosa	2017-04-27	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	RCV001147668	SCV001308505	benign	Retinal macular dystrophy type 2	2017-04-27	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.
Illumina Laboratory Services, Illumina	RCV001151003	SCV001312100	likely benign	Stargardt disease 4	2017-04-27	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.
GenomeConnect - Invitae Patient Insights Network	RCV001535742	SCV001749861	not provided	Retinitis pigmentosa 41; Cone-rod dystrophy 12; Retinal macular dystrophy type 2		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 01-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004539610	SCV004791152	uncertain significance	PROM1-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The PROM1 c.1345G>A variant is predicted to result in the amino acid substitution p.Val449Met. This variant was reported in an individual with Macular degeneration, age-related (Table 1, Kersten et al. 2018. PubMed ID: 30215852). This variant was also reported in an individual with Stargardt disease and his/her unaffected father, where both also carried variant of unknown significance in ABCA4 gene (Table 1 and 2, Lee et al. 2015. PubMed ID: 25910913). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygote. 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.