Submissions for variant NM_017882.3(CLN6):c.13C>T (p.Arg5Trp)

gnomAD frequency: 0.00003  dbSNP: rs886285802

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534403	SCV000628971	pathogenic	Neuronal ceroid lipofuscinosis	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the CLN6 protein (p.Arg5Trp). 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 neuronal ceroid lipofuscinosis (PMID: 21990111, 28831385, 33024953). 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: 457969). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CLN6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000665418	SCV000789538	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A	2017-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330752	SCV004037835	uncertain significance	not specified	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.13C>T (p.Arg5Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 80612 control chromosomes (gnomAD). c.13C>T has been reported in the literature in the compound heterozygous state together with a VUS in three siblings with clinical features of Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Vairo_2017), in trans with a pathogenic variant an individual who underwent whole genome sequencing, confirming a diagnosis of Kufs disease/Neuronal Ceroid-Lipofuscinosis (Talbot_2020), and in the heterozygous state in at least one other affected individual (Kousi_2012). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 33024953, 28831385). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000675966	SCV005081372	likely pathogenic	not provided	2024-05-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33144682, 28831385, 21990111, 33024953)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000665418	SCV005688715	likely pathogenic	Ceroid lipofuscinosis, neuronal, 6A	2023-12-26	criteria provided, single submitter	clinical testing	The CLN6 c.13C>T (p.Arg5Trp) variant has been reported in at least two unrelated individuals or families affected with Batten disease and is reported to segregate with disease in one family (Talbot J et al., PMID: 33024953; Vairo FP et al., PMID: 28831385). In all reported affected individuals, this variant was detected in trans to distinct pathogenic variants including one frameshift variant (Talbot J et al., PMID: 33024953; Vairo FP et al., PMID: 28831385). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by four submitters. This variant is only observed on 4/111,622 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in one of three arginines in a row that are required for endoplasmic reticulum targeting (Heine C et al., PMID: 17453415) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to CLN6 function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675966	SCV000801695	uncertain significance	not provided	2017-06-07	no assertion criteria provided	clinical testing