rs764109067
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001174150.2(ARL13B):c.599G>A(p.Arg200His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,822 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001174150.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARL13B | NM_001174150.2 | c.599G>A | p.Arg200His | missense_variant | 5/10 | ENST00000394222.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARL13B | ENST00000394222.8 | c.599G>A | p.Arg200His | missense_variant | 5/10 | 1 | NM_001174150.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727208
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2023 | Not observed at significant frequency 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: 18674751, 27894351, 27457812, 34645488, 34316023) - |
Joubert syndrome 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg200 amino acid residue in ARL13B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18674751). 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 ARL13B protein function. ClinVar contains an entry for this variant (Variation ID: 266096). This missense change has been observed in individual(s) with Joubert syndrome and related disorders (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 200 of the ARL13B protein (p.Arg200His). - |
Joubert syndrome and related disorders Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at