Submissions for variant NM_017882.3(CLN6):c.445C>T (p.Arg149Cys)

gnomAD frequency: 0.00006  dbSNP: rs747229909

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551912	SCV000628975	uncertain significance	Neuronal ceroid lipofuscinosis	2022-08-02	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 149 of the CLN6 protein (p.Arg149Cys). This variant is present in population databases (rs747229909, gnomAD 0.04%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111, 31741823). ClinVar contains an entry for this variant (Variation ID: 457972). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLN6 function (PMID: 32171521). This variant disrupts the p.Arg149 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 21549341, 30561534), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000551912	SCV002041755	likely pathogenic	Neuronal ceroid lipofuscinosis	2021-11-17	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.445C>T (p.Arg149Cys) 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 5.6e-05 in 251224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.445C>T has been reported in the literature as a non-informative genotype (second allele not specified) (example, Kousi_2012, Sleat_2016) and as a homozygous genotype in at-least three individuals (example Jiliani_2019) affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping but not all evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.