ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.49G>A (p.Gly17Ser) (rs763944821)

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Total submissions: 6
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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).
Invitae RCV001085897 SCV000628977 benign Neuronal ceroid lipofuscinosis 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000664742 SCV000788750 uncertain significance Neuronal ceroid lipofuscinosis 6 2017-01-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720755 SCV000851636 uncertain significance Seizures 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, 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 Clinical Services Laboratory,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.
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.

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