rs104894930
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000330.4(RS1):c.608C>T(p.Pro203Leu) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P203S) 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.608C>T | p.Pro203Leu | missense_variant | 6/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.512C>T | p.Pro171Leu | missense_variant | 4/4 | ||
CDKL5 | NM_001037343.2 | c.2714-3936G>A | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2714-3936G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.608C>T | p.Pro203Leu | missense_variant | 6/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2714-3936G>A | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2714-3936G>A | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.1099C>T | 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
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2022 | Published functional studies demonstrate a damaging effect with protein aggregation and defective secretion (Wu et al., 2003); Not observed in large population cohorts (gnomAD); 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: 9618178, 16167295, 19324861, 17515881, 30652005, 31456290, 33124204, 10450864, 10636740, 12746437) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | ClinVar contains an entry for this variant (Variation ID: 9895). This missense change has been observed in individuals with retinoschisis (PMID: 9618178, 10636740, 26356828, 28221463, 30652005). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the RS1 protein (p.Pro203Leu). 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. This variant disrupts the p.Pro203 amino acid residue in RS1. Other variant(s) that disrupt this residue have been observed in individuals with RS1-related conditions (PMID: 22245991, 28559085), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Juvenile retinoschisis Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2016 | - - |
Retinoschisis Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 03, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at