Submissions for variant NM_017882.3(CLN6):c.769A>G (p.Ser257Gly)

gnomAD frequency: 0.00475  dbSNP: rs151295143

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124343	SCV000167772	benign	not specified	2013-05-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000124343	SCV000247044	likely benign	not specified	2015-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV001079623	SCV000290390	benign	Neuronal ceroid lipofuscinosis	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000124343	SCV000313045	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000124343	SCV000341866	benign	not specified	2016-06-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312826	SCV000847949	benign	Inborn genetic diseases	2016-01-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001079623	SCV001280126	likely benign	Neuronal ceroid lipofuscinosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124343	SCV002500830	likely benign	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.769A>G (p.Ser257Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 251286 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 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 African or African-American origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=3) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675961	SCV000801690	likely benign	not provided	2017-09-27	no assertion criteria provided	clinical testing