ClinVar Miner

Submissions for variant NM_001042432.2(CLN3):c.1247A>G (p.Asp416Gly)

gnomAD frequency: 0.00001  dbSNP: rs386833703
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317069 SCV004020770 likely pathogenic Neuronal ceroid lipofuscinosis 2023-06-27 criteria provided, single submitter clinical testing Variant summary: CLN3 c.1247A>G (p.Asp416Gly) results in a non-conservative amino acid change to a highly conserved residue (HGMD) 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 4e-06 in 250758 control chromosomes (gnomAD). c.1247A>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kwon_2011, Lojewski_2014, Sleat_2017), and they were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact of the variant protein in iPSCs, finding reductions in TRPML1 activation, endolysosomal localization, and proteolysis, as well as expansion of the lysosomal compartment (Prat Castro_2022, Scotto Rosato_2022). The following publications have been ascertained in the context of this evaluation (PMID: 22013180, 24271013, 28792770, 36139381, 35929194). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000049664 SCV005058456 pathogenic Neuronal ceroid lipofuscinosis 3 2024-02-27 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049664 SCV000082071 probable-pathogenic Neuronal ceroid lipofuscinosis 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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