Submissions for variant NM_017882.3(CLN6):c.775G>A (p.Gly259Ser)

gnomAD frequency: 0.00002  dbSNP: rs150363441

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001235065	SCV001407729	likely pathogenic	Neuronal ceroid lipofuscinosis	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 259 of the CLN6 protein (p.Gly259Ser). This variant is present in population databases (rs150363441, gnomAD 0.01%). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 21990111, 35505348; Invitae). ClinVar contains an entry for this variant (Variation ID: 961382). 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.Gly259 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028, 31489614), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001375037	SCV001571713	likely pathogenic	Ceroid lipofuscinosis, neuronal, 6A	2021-02-12	criteria provided, single submitter	clinical testing	A homozygous missense variant in exon 7 of the CLN6 gene that results in the amino acid substitution of Serine for Glycine at codon 259 was detected. The observed variant c.775G>A (p.Leu83Val) has not been reported in the 1000 genomes and has a MAF of 0.0024% in gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
GeneDx	RCV001561994	SCV001784694	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing	Identified in a patient with suspected mitochondrial disease who also had a second CLN6 variant in trans (DaRe et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (G259C; G259V; G259D) reported in association with NCL in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24215330, 21990111)
Mendelics	RCV002246224	SCV002518720	pathogenic	Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002563820	SCV003733100	uncertain significance	Inborn genetic diseases	2022-11-17	criteria provided, single submitter	clinical testing	The c.775G>A (p.G259S) alteration is located in exon 7 (coding exon 7) of the CLN6 gene. This alteration results from a G to A substitution at nucleotide position 775, causing the glycine (G) at amino acid position 259 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV001375037	SCV005400854	likely pathogenic	Ceroid lipofuscinosis, neuronal, 6A	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.775G>A (p.Gly259Ser) variant in the CLN6 gene which is located in a mutational hot spot has been reported previously in compound heterozygous state in individuals affected with neuronal ceroid lipofuscinoses (Kousi et al., 2012; Cannelli et al., 2009). This variant has been reported to the ClinVar database as Pathogenic/ Likely pathogenic/ Uncertain significance. However, experimental studies on the pathogenicity of the variant are not available. This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. The amino acid Gly at position 259 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Gly259Ser in CLN6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.