ClinVar Genomic variation as it relates to human health

The homozygous p.Arg106ProfsTer26 variant in CLN6 was identified by our study in one individual with neuronal ceroid lipofuscinosis. The p.Arg106ProfsTer26 variant in CLN6 has been identified in 4 unrelated individuals with neuronal ceroid lipofuscinosis 6 (PMID: 23735787, PMID: 11727201) but has been identified in 0.02% (5/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs397515352). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. These 4 unrelated affected individuals were homozygotes (PMID: 23735787, PMID: 11727201), which increases the likelihood that the p.Arg106ProfsTer26 variant in CLN6 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 4081) and has been interpreted as pathogenic by multiple submitters. In vitro functional studies provide some evidence that the p.Arg106ProfsTer26 variant may impact protein function (PMID: 20020536, PMID: 15265688). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes neuronal ceroid lipofuscinosis (PMID: 11727201). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 106 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CLN6 gene is an established disease mechanism in autosomal recessive neuronal ceroid lipofuscinosis 6. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive neuronal ceroid lipofuscinosis 6. ACMG/AMP Criteria applied: PVS1, PS3, PM3 (Richards 2015).

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4081). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11727201). This variant is present in population databases (rs397515352, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg106Profs*26) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028).