rs104893792
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000539.3(RHO):āc.151G>Cā(p.Gly51Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51A) has been classified as Likely benign.
Frequency
Consequence
NM_000539.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RHO | NM_000539.3 | c.151G>C | p.Gly51Arg | missense_variant | 1/5 | ENST00000296271.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RHO | ENST00000296271.4 | c.151G>C | p.Gly51Arg | missense_variant | 1/5 | 1 | NM_000539.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Retinitis pigmentosa 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 1994 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 51 of the RHO protein (p.Gly51Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 8088850, 10967073, 28981474). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13047). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RHO function (PMID: 19913029, 25096327). For these reasons, this variant has been classified as Pathogenic. - |
RHO-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 09, 2023 | The RHO c.151G>C variant is predicted to result in the amino acid substitution p.Gly51Arg. This variant has been reported in multiple individuals with autosomal dominant retinitis pigmentosa and in several of these reports was found to segregate with disease within a kindred (al-Maghtheh et al. 1993. PubMed ID: 8401533; Vaithinathan et al. 1994. PubMed ID: 8088850; Dryja and McGee. 2000. PubMed ID: 10967073; Comander et al. 2017. PubMed ID: 28981474). Functional studies have shown that the p.Gly51Arg substitution causes protein misfolding and mislocalization (Rakoczy et al. 2011. PubMed ID: 21094163; Wan. 2019. PubMed ID: 30977563). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.151G>C (p.Gly51Arg) as pathogenic for autosomal dominant disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at