Submissions for variant NM_001042432.2(CLN3):c.1000C>T (p.Arg334Cys)

dbSNP: rs386833694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588369	SCV000697651	pathogenic	Neuronal ceroid lipofuscinosis	2024-06-24	criteria provided, single submitter	clinical testing	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 allele was found at a frequency of 4e-06 in 249336 control chromosomes (gnomAD). c.1000C>T has been reported in the literature in individuals affected with clinical features of neuronal ceroid-lipofuscinosis (Batten Disease; example: Pohl_2007, Smirnov_2021, Munroe_1997). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1001G>A, p.Arg334His) supporting the critical relevance of codon 334 to CLN3 protein function. In functional studies, the variant was found to affect normal protein function (Haines_2009). The following publications have been ascertained in the context of this evaluation (PMID: 9311735, 17868323, 19132115, 33507216). ClinVar contains an entry for this variant (Variation ID: 56243). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588369	SCV001232832	pathogenic	Neuronal ceroid lipofuscinosis	2023-11-21	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000049655	SCV004214318	likely pathogenic	Neuronal ceroid lipofuscinosis 3	2024-03-12	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049655	SCV000082062	probable-pathogenic	Neuronal ceroid lipofuscinosis 3		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000049655	SCV001132155	likely pathogenic	Neuronal ceroid lipofuscinosis 3	2018-10-16	no assertion criteria provided	clinical testing