Submissions for variant NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)

gnomAD frequency: 0.00002  dbSNP: rs765893479

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001222663	SCV001394774	pathogenic	Neuronal ceroid lipofuscinosis	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 59 of the CLN3 protein (p.Ala59Thr). This variant is present in population databases (rs765893479, gnomAD 0.004%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 30446867; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 950856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN3 protein function. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001810499	SCV002060092	uncertain significance	Neuronal ceroid lipofuscinosis 3	2021-11-03	criteria provided, single submitter	clinical testing	NM_001042432.1(CLN3):c.175G>A(A59T) is a missense variant classified as a variant of uncertain significance in the context of CLN3-related neuronal ceroid lipofuscinosis. A59T has been observed in cases with relevant disease (PMID: 30446867). Functional assessments of this variant are available in the literature (PMID: 30446867). A59T has been observed in population frequency databases (gnomAD: AFR <0.004%). In summary, there is insufficient evidence to classify NM_001042432.1(CLN3):c.175G>A(A59T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001222663	SCV002074336	likely pathogenic	Neuronal ceroid lipofuscinosis	2022-01-19	criteria provided, single submitter	clinical testing	Variant summary: CLN3 c.175G>A (p.Ala59Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249916 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.175G>A has been reported in the literature in an individual with late-onset non-syndromic CLN3-associated retinitis pigmentosa (Zhang_2018, Chen_2019). Additionally, one clinical diagnostic lab has reported the variant to be observed in individual(s) with retinitis pigmentosa which has been observed to segregate with diease in related individuals (Invitae via ClinVar). In functional studies, the variant was reported to lead to altered splicing (Chen_2019). Correction of the c.175G>A variant restored CLN3 mRNA and protein expression, prevented accumulation of SCMAS, and reduced vacuolization of photoreceptor inner segments (Zhang_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002462842	SCV002756999	likely pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant causes altered splicing of the CLN3 pre-mRNA, protein expression, cell histology, and SCMAS expression (Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27104957, 29753273, 33507216, 32441891, 33497524, 30446867)
Ambry Genetics	RCV003346386	SCV004075560	pathogenic	Inborn genetic diseases	2023-09-12	criteria provided, single submitter	clinical testing	The c.175G>A (p.A59T) alteration is located in exon 4 (coding exon 3) of the CLN3 gene. This alteration results from a G to A substitution at nucleotide position 175, causing the alanine (A) at amino acid position 59 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/281296) total alleles studied. The highest observed frequency was 0.004% (1/24784) of African alleles. This alteration was detected in conjunction with another alteration in CLN3 in multiple individuals with CLN3- related disorders (Chen, 2019; external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV001810499	SCV004214303	likely pathogenic	Neuronal ceroid lipofuscinosis 3	2023-10-25	criteria provided, single submitter	clinical testing