chr15-68211853-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000249806.11(CLN6):c.308G>A(p.Arg103Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,410 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. R103W) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000249806.11 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN6 | NM_017882.3 | c.308G>A | p.Arg103Gln | missense_variant | 4/7 | ENST00000249806.11 | NP_060352.1 | |
CLN6 | NM_001411068.1 | c.404G>A | p.Arg135Gln | missense_variant | 4/7 | NP_001397997.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN6 | ENST00000249806.11 | c.308G>A | p.Arg103Gln | missense_variant | 4/7 | 1 | NM_017882.3 | ENSP00000249806 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250396Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135368
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461312Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726908
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 103 of the CLN6 protein (p.Arg103Gln). This variant is present in population databases (rs154774634, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of neuronal ceroid lipofuscinosis (PMID: 21549341, 30561534, 35505348). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30600). 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 not expected to disrupt CLN6 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg103 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18846690, 27903347). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2024 | Variant summary: CLN6 c.308G>A (p.Arg103Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250396 control chromosomes. c.308G>A has been reported in the literature in compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and this variant was co-segregated with disease (example: Arsov_ 2011, Berkovic_2019. Rus_2022). These data indicate that the variant is likely to be associated with disease. Additionally, another missense variant at the same codon, R103W, has been found in patients with Neuronal Ceroid-Lipofuscinosis in the Human Gene Mutation Database, indicating the arginine residue is critical for CLN6 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21549341, 30561534, 35505348). ClinVar contains an entry for this variant (Variation ID: 30600). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | SNPedia | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 15, 2021 | - - |
Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 13, 2011 | - - |
Ceroid lipofuscinosis, neuronal, 6A Uncertain:1
Uncertain significance, flagged submission | clinical testing | Counsyl | May 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at