ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1056G>T (p.Gln352His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000817490 SCV000958054 likely pathogenic Neuronal ceroid lipofuscinosis 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 352 of the CLN3 protein (p.Gln352His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 14 of the CLN3 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Batten disease (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It has also been reported in an unrelated affected individual in combination with a pathogenic CLN3 variant (PMID: 15818814). 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 C15"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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