ClinVar Genomic variation as it relates to human health

The homozygous p.Tyr221Ser variant in CLN6 was identified by our study in one individual with neuronal ceroid lipofuscinosis. The p.Tyr221Ser variant in CLN6 has been reported in 1 Argentinian individual and 1 Turkish Individual with neuronal ceroid lipofuscinosis (PMID: 12815591, 21990111), and has been identified in 0.01624% (5/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764571295). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This missense variant affects the same residue as a variant, p.Tyr221Cys, reported in association with neuronal ceroid lipofuscinosis in 2 siblings and 1 unrelated individual in the literature, slightly supporting that a change at this residue may not be tolerated (PMID: 19135028). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM5_Supporting (Richards 2015).

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:19135028). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.895>=0.6, 3CNET: 0.884>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000278). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 221 of the CLN6 protein (p.Tyr221Ser). This variant is present in population databases (rs764571295, gnomAD 0.02%). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 12815591, 21990111). ClinVar contains an entry for this variant (Variation ID: 560342). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Tyr221 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: CLN6 c.662A>C (p.Tyr221Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251004 control chromosomes (gnomAD). c.662A>C has been reported in the literature in the heterozygous state in an Argentinian individual (Sharp_2003), in the homozygous state in two Turkish individuals (Kousi_2012), and in at least four other individuals (including a sibling pair) where the zygosity was not explicitly specified (Rus_2022), all of whom were affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same codon, p.Tyr221Cys, has been reported in affected individuals (HGMD database), suggesting this residue may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 35505348, 12815591). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The c.662A>C(p.Tyr221Ser) variant in CLN6 gene has been reported in compound heterozygous state in individual affected with neuronal ceroid lipofuscinosis(Sharp et al., 2003). This variant is reported with the allele frequency 0.002% in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Uncertain significance. The amino acid Tyr at position 221 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Tyr221Ser in CLN6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

Late Infantile NCL