ClinVar Miner

Submissions for variant NM_018941.4(CLN8):c.374A>G (p.Asn125Ser)

gnomAD frequency: 0.00083  dbSNP: rs142269885
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656837 SCV000240718 likely benign not provided 2021-04-29 criteria provided, single submitter clinical testing Reported in the homozygous state in an individual with lissencephaly, intellectual disability, hyperreflexia, spasticity, generalized seizures, and tetralogy of Fallot who also had a homozygous variant in the RELN gene (Alfares et al., 2017); Reported as a pathogenic variant; however, it was identified in an individual who did not have epilepsy or any reported features of NCL, and who did not have a second detectable pathogenic variant in the CLN8 gene (Kousi et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21990111, 28454995, 29961513, 30548430, 30919163)
Eurofins NTD LLC (GA) RCV000656837 SCV000342696 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000187142 SCV000594157 uncertain significance not specified 2015-08-10 criteria provided, single submitter clinical testing
Invitae RCV001080578 SCV000628988 likely benign Neuronal ceroid lipofuscinosis 2020-12-04 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000677331 SCV000803575 likely benign Neuronal ceroid lipofuscinosis 8 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Benign, for Ceroid lipofuscinosis, neuronal, 8, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Allele frequency is greater than expected for disorder.
Ambry Genetics RCV000717803 SCV000848663 uncertain significance Seizure 2019-03-18 criteria provided, single submitter clinical testing The p.N125S variant (also known as c.374A>G), located in coding exon 1 of the CLN8 gene, results from an A to G substitution at nucleotide position 374. The asparagine at codon 125 is replaced by serine, an amino acid with highly similar properties. In one study, this alteration was listed as as a neuronal ceroid-lipofuscinoses (NCL) associated mutation; however, there was no phenotypic information provided on the individual in which it was detected (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63). This variant was also identified in the homozygous state in an individual with NCL and lissencephaly; this individual was also homozygous for a frameshift variant in the RELN gene (Alfares A et al. Mol. Genet. Metab., 2017 06;121:91-95). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
New York Genome Center RCV000677331 SCV001480381 uncertain significance Neuronal ceroid lipofuscinosis 8 2020-05-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000677331 SCV001524552 uncertain significance Neuronal ceroid lipofuscinosis 8 2019-02-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories,Mayo Clinic RCV000656837 SCV001714261 uncertain significance not provided 2019-06-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000187142 SCV002547515 likely benign not specified 2022-05-20 criteria provided, single submitter clinical testing Variant summary: CLN8 c.374A>G (p.Asn125Ser) results in a conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of 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 0.00097 in 251482 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLN8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.00087), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Co-occurrences with at least one other pathogenic variant has been reported in an individual homozygous for the variant of interest and homozygous for a RELN variant (c.9841del, p.Ala3281fs, Alfares_2017), providing supporting evidence for a benign role. To our knowledge, no individuals affected with Neuronal Ceroid-Lipofuscinosis and no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as of uncertain significance, one as likely pathogenic, and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000677331 SCV001133078 likely pathogenic Neuronal ceroid lipofuscinosis 8 2019-09-26 no assertion criteria provided clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251946 SCV001427692 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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