Submissions for variant NM_017882.3(CLN6):c.5A>G (p.Glu2Gly)

gnomAD frequency: 0.00042  dbSNP: rs3743088

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187109	SCV000240684	uncertain significance	not provided	2018-07-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CLN6 gene. The E2G variant has beenreported previously in the homozygous state in an individual with late-infantile neuronal ceroidlipofuscinosis (Di Fruscio et al., 2015). The E2G variant is observed in 13/1008 (1.3%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The E2G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R5W, R6T) have been reported in the Human GeneMutation Database in association with NCL (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082320	SCV000628980	benign	Neuronal ceroid lipofuscinosis	2025-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000664477	SCV000788440	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A	2017-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311263	SCV000846586	uncertain significance	Inborn genetic diseases	2019-03-26	criteria provided, single submitter	clinical testing	The p.E2G variant (also known as c.5A>G), located in coding exon 1 of the CLN6 gene, results from an A to G substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by glycine, an amino acid with similar properties. This variant was reported as homozygous in an individual with neuronal ceroid lipofuscinosis (Di Fruscio G et al. Autophagy, 2015;11:928-38). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001082320	SCV001278036	likely benign	Neuronal ceroid lipofuscinosis	2017-08-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000187109	SCV001713715	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731421	SCV001984484	likely benign	Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2020-07-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000187109	SCV003832405	uncertain significance	not provided	2020-07-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003538	SCV005631004	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2024-04-11	criteria provided, single submitter	clinical testing