Submissions for variant NM_017882.3(CLN6):c.407G>A (p.Arg136His)

gnomAD frequency: 0.00001  dbSNP: rs769701646

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000454168	SCV000537961	likely pathogenic	Abnormal brain morphology		criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000499595	SCV000594156	uncertain significance	not specified	2015-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379796	SCV001577667	pathogenic	Neuronal ceroid lipofuscinosis	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 136 of the CLN6 protein (p.Arg136His). This variant is present in population databases (rs769701646, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 26075876, 26539891, 27903347, 30561534, 34868216). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 402184). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN6 protein function. This variant disrupts the p.Arg136 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224283	SCV003919809	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2021-03-30	criteria provided, single submitter	clinical testing	CLN6 NM_017882 exon 4 p.Arg136His (c.407G>A): This variant has been reported in the literature in the homozygous state in one individual with intellectual disability, cerebellar atrophy, and ataxia, as well as in the compound heterozygous state with another CLN6 variant of uncertain significance in one individual with juvenile dementia and epilepsy (Karaca 2015 PMID:26539891, Di Fruscio 2015 PMID:26075876). This variant is present in 0.008% (11/129134) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-68504092-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar (Variation ID:402184). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001379796	SCV003933968	pathogenic	Neuronal ceroid lipofuscinosis	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.407G>A (p.Arg136His) 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 4e-05 in 251264 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.407G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and in one individual with clinical features within the spectrum of the disease phenotype (e.g. Karaca_2015, DiFruscio_2015, Berkovic_2019, Nicolaou_2021, Rus_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30561534, 26075876, 26539891, 34868216, 35505348). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.