16-28482161-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001042432.2(CLN3):c.1000C>T(p.Arg334Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. R334H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042432.2 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 |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.1000C>T | p.Arg334Cys | missense_variant | 14/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.1000C>T | p.Arg334Cys | missense_variant | 14/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249336Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134876
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461512Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727044
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 3 Pathogenic:3
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 31, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 16, 2018 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2019 | Variant summary: CLN3 c.1000C>T (p.Arg334Cys) 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 was absent in 275064 control chromosomes (gnomAD). c.1000C>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease). These data indicate that the variant may be associated with disease. The c.1000C>T variant has been reported in the literature in several individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease), indicating that the variant may be associated with disease. Additionally, a variant affecting the same codon c.1001G>A (p.R334H) was also observed in 4 families with classical JNCL phenotype, indicating residue 334 is likely critical for normal function of the CLN3 protein. The variant is located in the third lumenal region on the predicted lumenal face of a putative amphipathic helix, and all proteins mutated in this region were defective in function observed by a functional study (Haines_2009), suggesting this region has a significant effect on the protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 334 of the CLN3 protein (p.Arg334Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with isolated retinitis pigmentosa and/or neuronal ceroid lipofuscinosis (PMID: 9311735, 17475770, 21990111, 25976102, 33507216, 33921607). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56243). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN3 protein function. Experimental studies have shown that this missense change affects CLN3 function (PMID: 10924275, 11589014, 17475770, 19132115). This variant disrupts the p.Arg334 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9311735, 20187884, 21499717, 21990111, 23539563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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