Submissions for variant NM_017882.3(CLN6):c.49G>A (p.Gly17Ser)

gnomAD frequency: 0.00002  dbSNP: rs763944821

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187110	SCV000240685	uncertain significance	not provided	2018-11-12	criteria provided, single submitter	clinical testing	p.Gly17Ser (GGC>AGC): c.49 G>A in exon 1 of the CLN6 gene (NM_017882.2). The G17S missense substitution was reported as a novel disease-causing mutation (Kousi et al., 2012); however, it was identified in a patient who did not have a second detectable mutation in the CLN6 gene, and no additional information was provided about the patient's phenotype. G17S was not observed in approximately 1,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G17S 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts the G17S variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085897	SCV000628977	benign	Neuronal ceroid lipofuscinosis	2024-01-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000664742	SCV000788750	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A	2017-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317081	SCV000851636	uncertain significance	Inborn genetic diseases	2020-01-06	criteria provided, single submitter	clinical testing	The p.G17S variant (also known as c.49G>A), located in coding exon 1 of the CLN6 gene, results from a G to A substitution at nucleotide position 49. The glycine at codon 17 is replaced by serine, an amino acid with similar properties. This alteration was reported as a novel disease-causing mutation in the heterozygous state in one individual; however, a second alteration was not reported and no clinical information was provided for this individual (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001085897	SCV001278033	uncertain significance	Neuronal ceroid lipofuscinosis	2017-09-26	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228805	SCV002511832	likely benign	not specified	2022-04-20	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.49G>A (p.Gly17Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 81240 control chromosomes, predominantly at a frequency of 0.0039 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.49G>A has been reported in the literature in at least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Kousi_2012). The report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000187110	SCV001550369	likely benign	not provided		no assertion criteria provided	clinical testing	The CLN6 p.Gly17Ser variant was identified in a patient from Turkey with neuronal ceroid lipofuscinose (Kousi_2012_PMID:21990111). The variant was identified in dbSNP (ID: rs763944821) and ClinVar (classified as benign by Invitae and as a VUS by Counsyl, Ambry Genetics and GeneDx) but was not identified in LOVD 3.0. The variant was identified in control databases in 68 of 112310 chromosomes (2 homozygous) at a frequency of 0.0006055 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 67 of 17028 chromosomes (freq: 0.003935) and Other in 1 of 3468 chromosomes (freq: 0.000288), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The p.Gly17 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.