rs267606737
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042432.2(CLN3):c.597C>A(p.Tyr199Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,194 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042432.2 stop_gained
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.597C>A | p.Tyr199Ter | stop_gained | 9/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.597C>A | p.Tyr199Ter | stop_gained | 9/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247752Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134298
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726884
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 3 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 06, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2019 | The Y199X nonsense variant in the CLN3 gene has been reported previously in the homozygous state in five siblings with juvenile neuronal ceroid lipofuscinosis (Sarpong et al., 2009). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y199X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, Y199X is considered a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 14, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Very strong co-segregation with disease in affected individuals from a single family. - |
Ceroid lipofuscinosis, neuronal, 3, protracted Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2009 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change creates a premature translational stop signal (p.Tyr199*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is present in population databases (rs267606737, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with protracted juvenile neuronal ceroid lipofuscinosis (PMID: 19489875, 22013180). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3557). 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