chrX-18642012-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000330.4(RS1):c.667T>C(p.Cys223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C223Y) has been classified as Pathogenic.
Frequency
Consequence
NM_000330.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.667T>C | p.Cys223Arg | missense_variant | 6/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.571T>C | p.Cys191Arg | missense_variant | 4/4 | ||
CDKL5 | NM_001037343.2 | c.2714-3995A>G | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2714-3995A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.667T>C | p.Cys223Arg | missense_variant | 6/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2714-3995A>G | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2714-3995A>G | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.1158T>C | non_coding_transcript_exon_variant | 5/5 | 1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Juvenile retinoschisis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2021 | This sequence change replaces cysteine with arginine at codon 223 of the RS1 protein (p.Cys223Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with retinoschisis (PMID: 10533068, 30652005, Invitae). ClinVar contains an entry for this variant (Variation ID: 9893). 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 RS1 protein function. Experimental studies have shown that this variant affects RS1 protein function (PMID: 16361673). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at