NM_006017.3:c.1117C>T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_006017.3(PROM1):c.1117C>T(p.Arg373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006017.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456900Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725068
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:8
PROM1: PP1:Strong, PS4, PM2, PP4, PS3:Supporting, BP4 -
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Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein mislocalization (PMID: 18654668); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28840994, 29847639, 12657606, 23161075, 25356976, 26667666, 25133751, 28559085, 32531858, 31144483, 31129250, 10205271, 25590640, 27624628, 28076437, 27160483, 26103963, 20393116, 28041643, 23891399, 31054281, 32820593, 32534057, 31736247, 32581362, 34008001, 33090715, 30653986, 22581970, 22183351, 20859302, 29555955, 36259723, 38072963, 36460718, 31213501, 36729443, 36819107, 36909829, 33749171, 36284460, 37734845, 30926958, 18654668) -
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the PROM1 protein (p.Arg373Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant forms of retinal dystrophy (PMID: 18654668, 20393116, 22183351, 28559085, 29847639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5610). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PROM1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROM1 function (PMID: 18654668). For these reasons, this variant has been classified as Pathogenic. -
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Retinal dystrophy Pathogenic:4
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Retinal macular dystrophy type 2 Pathogenic:3
Variant is not found in gnomAD genomes, and frequency in gnomAD exomes is < 0.00001 (PM2). Functional study shows that this variant affects PROM1 function (PS3, PMID: 18654668). There is cosegregation with the disease phenotypes in multiple families observed in multiple studies (PP1_str, internal data, PMID: 20393116;28041643;25356976;22183351;18654668) -
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Clinical significance based on ACMG v2.0 -
Stargardt disease 4;C2675210:Cone-rod dystrophy 12;C2677516:Retinitis pigmentosa 41;C4749334:Retinal macular dystrophy type 2 Pathogenic:2
PM2_Supporting+PS2_Supporting+PS4_Moderate+PP1_Strong+PP4+PS3 -
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Stargardt disease 4 Pathogenic:1
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Macular dystrophy Pathogenic:1
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Cone-rod dystrophy 12 Pathogenic:1
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Retinitis pigmentosa Pathogenic:1
The p.Arg373Cys variant in PROM1 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, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Stargardt disease Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at