Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001316419 | SCV001507038 | pathogenic | Neuronal ceroid lipofuscinosis | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the CLN6 mRNA. The next in-frame methionine is located at codon 66. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017289). This variant disrupts a region of the CLN6 protein in which other variant(s) (p.Arg62Cys) have been determined to be pathogenic (PMID: 12815591, 19135028, 31216804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001316419 | SCV004100032 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2023-09-20 | criteria provided, single submitter | clinical testing | Variant summary: CLN6 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. Second in-frame Met is located in codon 66 and variants upstream of this codon were found in patients with neuronal ceroid lipofuscinosis in HGMD and classified as pathogenic in ClinVar. The variant was absent in 80306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3G>A in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |