Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001004876 | SCV001164358 | uncertain significance | Ceroid lipofuscinosis, neuronal, 6A | 2018-12-03 | criteria provided, single submitter | research | The homozygous p.Tyr221Cys variant in CLN6 was identified by our study in one individual with neuronal ceroid lipofuscinosis. The p.Tyr221Cys variant in CLN6 has been reported in 3 Sardinian individuals and 1 Turkish individual with neuronal ceroid lipofuscinosis and segregated with disease in 2 affected relatives from 1 family (PMID: 19135028, 19201763), but has been identified in 0.009746% (3/30782) 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 1 Argentinian individual and 1 Turkish Individual with neuronal ceroid lipofuscinosis, slightly supporting that a change at this residue may not be tolerated (PMID: 12815591, 21990111). 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). |
| Invitae | RCV002549262 | SCV003442996 | uncertain significance | Neuronal ceroid lipofuscinosis | 2022-06-20 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 221 of the CLN6 protein (p.Tyr221Cys). This variant is present in population databases (rs764571295, gnomAD 0.01%). This missense change has been observed in individuals with variant late-infantile neuronal ceroid lipofuscinosis (v-LINCL) (PMID: 19135028). ClinVar contains an entry for this variant (Variation ID: 813907). 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"). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002549262 | SCV005077601 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2024-04-18 | criteria provided, single submitter | clinical testing | Variant summary: CLN6 c.662A>G (p.Tyr221Cys) 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 1.6e-05 in 251004 control chromosomes. c.662A>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Cannelli_2009, Santorelli_2013). 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. The following publications have been ascertained in the context of this evaluation (PMID: 19135028, 23374165). ClinVar contains an entry for this variant (Variation ID: 813907). Based on the evidence outlined above, the variant was classified as likely pathogenic. |