ClinVar Miner

Submissions for variant NM_001042432.2(CLN3):c.883G>A (p.Glu295Lys)

gnomAD frequency: 0.00003  dbSNP: rs121434286
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000811923 SCV000952214 pathogenic Neuronal ceroid lipofuscinosis 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 295 of the CLN3 protein (p.Glu295Lys). This variant is present in population databases (rs121434286, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy and neuronal ceroid lipofuscinosis (PMID: 9311735, 9450775, 24154662, 27486012). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3556). 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 CLN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN3 function (PMID: 10332042, 16291725, 19132115). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000055839 SCV000965804 pathogenic Neuronal ceroid lipofuscinosis 3 2015-01-01 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000055839 SCV001162797 pathogenic Neuronal ceroid lipofuscinosis 3 2019-06-11 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074385 SCV001239963 pathogenic Retinal dystrophy 2019-08-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV002512720 SCV003745354 pathogenic Inborn genetic diseases 2020-11-04 criteria provided, single submitter clinical testing The c.883G>A (p.E295K) alteration is located in exon 12 (coding exon 11) of the CLN3 gene. This alteration results from a G to A substitution at nucleotide position 883, causing the glutamic acid (E) at amino acid position 295 to be replaced by a lysine (K). Based on data from the Genome Aggregation Database (gnomAD) database, the CLN3 c.883G>A alteration was observed in 0.0025% (7/282860) of total alleles studied. This alteration has been detected in multiple affected individuals with a second disease-causing allele (Munroe, 1997; Wisniewski, 1998; Aberg, 2009) and has been reported to be associated with protracted disease when in trans with the common 1.02kb deletion in CLN3 (Cotman, 2012). This amino acid position is well conserved in available vertebrate species. The p.E295K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics RCV000055839 SCV004214324 pathogenic Neuronal ceroid lipofuscinosis 3 2024-03-07 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV001074385 SCV005072672 pathogenic Retinal dystrophy 2020-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV004791194 SCV005414345 pathogenic not provided 2024-03-15 criteria provided, single submitter clinical testing PP3, PP4, PM2_moderate, PM3_strong, PS3, PS4_moderate
OMIM RCV000003735 SCV000023898 pathogenic Ceroid lipofuscinosis, neuronal, 3, protracted 1998-01-01 no assertion criteria provided literature only
GeneReviews RCV000055839 SCV000086831 pathologic Neuronal ceroid lipofuscinosis 3 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001270479 SCV001450771 pathogenic early onset and severe retinal dystrophy no assertion criteria provided research

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