Submissions for variant NM_017882.3(CLN6):c.923G>C (p.Ser308Thr)

gnomAD frequency: 0.00169  dbSNP: rs143578698

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724552	SCV000232276	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724552	SCV000240683	likely benign	not provided	2020-07-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25359263, 30548430, 21549341)
Invitae	RCV001080133	SCV000560152	benign	Neuronal ceroid lipofuscinosis	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000187108	SCV000594155	uncertain significance	not specified	2016-11-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515242	SCV000611459	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A; Adult neuronal ceroid lipofuscinosis	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314666	SCV000847720	uncertain significance	Inborn genetic diseases	2018-11-11	criteria provided, single submitter	clinical testing	The p.S308T variant (also known as c.923G>C), located in coding exon 7 of the CLN6 gene, results from a G to C substitution at nucleotide position 923. The serine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was detected in conjunction with two additional CLN6 alterations c.150C>G (p.T50*) and c.231C>G (p.N77K) in an individual with Kufs disease; however, the phase of these three alterations was not confirmed (Arsov T et al. Am. J. Hum. Genet., 2011 May;88:566-73). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001080133	SCV001277914	uncertain significance	Neuronal ceroid lipofuscinosis	2017-04-27	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724552	SCV001713712	uncertain significance	not provided	2020-11-23	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002054140	SCV002496055	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2021-03-30	criteria provided, single submitter	clinical testing	CLN6 NM_017882.2 exon 7 p.Ser308Thr (c.923G>C): This variant has not been reported in the literature and is present in 0.3% (435/128540) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-68500491-C-G). This variant is present in ClinVar (Variation ID:198573). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003398902	SCV004103163	uncertain significance	CLN6-related condition	2023-05-31	criteria provided, single submitter	clinical testing	The CLN6 c.923G>C variant is predicted to result in the amino acid substitution p.Ser308Thr. This variant has been previously reported along with two other variants in the CLN6 gene in an individual with major adult form of neuronal ceroid lipofuscinosis (Family Ku8, Arsov et al. 2011. PubMed ID: 21549341). This variant was also observed in the heterozygous state in a cohort of individuals with suspected lysosomal storage disease and reported as a variant of uncertain significance (Table 3, Gheldof et al. 2019. PubMed ID: 30548430). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-68500491-C-G), which is more common than expected for a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000724552	SCV004700280	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CLN6: BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724552	SCV001930580	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724552	SCV001965572	likely benign	not provided		no assertion criteria provided	clinical testing