13-76995077-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_006493.4(CLN5):c.188G>A(p.Arg63His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,730 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 (★★).
Frequency
Consequence
NM_006493.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.188G>A | p.Arg63His | missense_variant | Exon 2 of 4 | ENST00000377453.9 | NP_006484.2 | |
CLN5 | NM_001366624.2 | c.188G>A | p.Arg63His | missense_variant | Exon 2 of 5 | NP_001353553.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.188G>A | p.Arg63His | missense_variant | Exon 2 of 4 | 1 | NM_006493.4 | ENSP00000366673.5 | ||
ENSG00000283208 | ENST00000638147.2 | c.188G>A | p.Arg63His | missense_variant | Exon 2 of 5 | 5 | ENSP00000490953.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251186Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135764
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461568Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727078
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Pathogenic:4
PS3, PM3, PM5, PM2_Supporting, PP4 -
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Neuronal ceroid lipofuscinosis Pathogenic:3
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). This variant is present in population databases (rs104894386, gnomAD 0.003%). This missense change has been observed in individuals with juvenile onset neuronal ceroid lipofuscinosis (PMID: 15728307, 28542837, 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2567). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CLN5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been observed in individuals with CLN5-related conditions (PMID: 30078242), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251186 control chromosomes (gnomAD). c.188G>A has been reported in the literature in the homozygous state in two siblings and in at least one other unrelated individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Pineda-Trujilo_2005, Zhou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant protein primarily localizes to the ER as opposed to the lysosome, however, it does not allow convincing conclusions about the variant effect (Schmiedt_2010). Other variants affecting the same amino acid (i.e. p.Arg63Cys, p.Arg63Pro) have been reported in association with Neuronal Ceroid-Lipofuscinosis in the HGMD database, suggesting Arg63 may be important for protein function, but this has yet to be determined conclusively. The following publications have been ascertained in the context of this evaluation (PMID: 15728307, 20052765, 30078242). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect as the R112H variant produces a protein unable to exit the endoplasmic reticulum (Schmiedt et al., 2010); 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: 21990111, 15728307, 33792748, 30264640, 28542837, 30078242, 32983231, 20052765) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at