rs104894928
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000330.4(RS1):c.214G>C(p.Glu72Gln) 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. E72D) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.214G>C | p.Glu72Gln | missense_variant | 4/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.118G>C | p.Glu40Gln | missense_variant | 2/4 | ||
CDKL5 | NM_001037343.2 | c.2797+1213C>G | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2797+1213C>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.214G>C | p.Glu72Gln | missense_variant | 4/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2797+1213C>G | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2797+1213C>G | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.705G>C | non_coding_transcript_exon_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 25, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu72 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 20809529, 28272453, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 98916). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 11295123, 19390641, 28348004). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 72 of the RS1 protein (p.Glu72Gln). - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28348004, 33460243, 19390641, 11295123) - |
Juvenile retinoschisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at