Submissions for variant NM_017882.3(CLN6):c.406C>T (p.Arg136Cys)

dbSNP: rs1012449574

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813418	SCV000953777	pathogenic	Neuronal ceroid lipofuscinosis	2024-01-18	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 136 of the CLN6 protein (p.Arg136Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 19135028, 35505348; Invitae). 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: 656898). 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 CLN6 protein function. This variant disrupts the p.Arg136 nucleotide in the CLN6 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002249523	SCV002518723	pathogenic	Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000813418	SCV004122708	pathogenic	Neuronal ceroid lipofuscinosis	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.406C>T (p.Arg136Cys) 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 251298 control chromosomes (gnomAD). c.406C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Cannelli_2009, Rus_2022, Refeat_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19135028, 36435927, 35505348). A different variant affecting the same codon (c.407G>A, p.Arg136His) is classified pathogenic internally. This suggests that this residue may be fucntionally important. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and VUS(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV003145176	SCV003832407	uncertain significance	not provided	2020-07-30	flagged submission	clinical testing