Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001286110.2(CLN3):c.-83A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 16-28491759-T-G is Pathogenic according to our data. Variant chr16-28491759-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 56257.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28491759-T-G is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with neuronal ceroid lipofuscinosis and may be associated with a milder phenotype (PMID: 21990111, 32154056). ClinVar contains an entry for this variant (Variation ID: 56257). For these reasons, this variant has been classified as Pathogenic. -
Neuronal ceroid lipofuscinosis 3 Pathogenic:1
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)