ClinVar Genomic variation as it relates to human health

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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.

See Variant Classification Assertion Criteria.

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.

This variant has been reported in the literature in the homozygous state in at least 1 individual with a complex neurological phenotype; this individual also carried a homozygous frameshift variant in a different neurological gene (RELN). This variant was also identified in the heterozygous state in 1 individual with suspicion of a lysosomal storage disorder and this variant was also identified in 1 individual with "CLN8-related disease", though no other variants were reported in the individual (Kousi 2012 PMID: 21990111, Alfares 2017 PMID:28454995, Gheldof 2019 PMID:30548430). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.1% (19/15276) (https://gnomad.broadinstitute.org/variant/8-1771428-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID:205207). This variant amino acid Serine (Ser) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Variant classified as Likely benign and reported on 07-01-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.