Submissions for variant NM_001042432.2(CLN3):c.565G>T (p.Gly189Trp)

dbSNP: rs386833731

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001119059	SCV001277399	uncertain significance	Neuronal ceroid lipofuscinosis 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
3billion, Medical Genetics	RCV001119059	SCV002521677	uncertain significance	Neuronal ceroid lipofuscinosis 3	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.81). A different missense change at the same codon (p.Gly189Arg) has been reported to be associated with CLN3 related disorder (ClinVar ID: VCV000056282 / PMID: 21990111). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences	RCV001119059	SCV004100320	pathogenic	Neuronal ceroid lipofuscinosis 3	2023-10-17	criteria provided, single submitter	clinical testing	The missense variant NM_001042432.2:c.565G>T causes a change at the same amino acid residue as a previously established pathogenic variant. The NP_001035897.1:p.Gly189Trp variant is previously reported to ClinVar (Accession:VCV000886715.5 ) as a variant of uncertain significance. The NP_001035897.1:p.Gly189Trp variant is novel (not in any individuals) in 1000 Genomes as well as in our inhouse database. Although the variant is present at 0.0000% in gnomAD, it has the flag "RF" and may not represent the true population frequency. There is a large physicochemical difference between glycine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 2 variants within 6 amino acid positions of the variant p.Gly189Trp have been shown to be pathogenic, while none have been shown to be benign. The p.Gly189Trp missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 189 of CLN3 is conserved in all mammalian species. The nucleotide c.565 in CLN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. The p.Gly189Trp variant is observed in this individual in compound heterozygous state with a previously established Likely pathogenic variant (VCV000948224.5). In addition, the proband's phenotype matches to that of the disorder caused by pathogenic variants in CLN3. For these reasons, this variant has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005056903	SCV005691302	uncertain significance	Neuronal ceroid lipofuscinosis	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the CLN3 protein (p.Gly189Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 886715). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Gly189 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990111, 24154662; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.