Submissions for variant NM_001042432.2(CLN3):c.988G>A (p.Val330Ile)

gnomAD frequency: 0.00004  dbSNP: rs386833744

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187016	SCV000240589	likely pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.V330I causes protein subcellular mislocalization (Scotto et al., 2022); Reported in a patient with retinal disease who harbored a second CLN3 variant in unknown phase (Ku et al., 2017); Reported in a patient with retinitis pigmentosa (Carss et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22013180, 19132115, 32581362, 32441891, 35929194, 9311735, 30380624, 28041643, 28542676)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812919	SCV000953249	pathogenic	Neuronal ceroid lipofuscinosis	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 330 of the CLN3 protein (p.Val330Ile). This variant is present in population databases (rs386833744, gnomAD 0.008%). This missense change has been observed in individuals with retinitis pigmentosa and/or rod-cone dystrophy (PMID: 28542676; Invitae). ClinVar contains an entry for this variant (Variation ID: 205095). 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) performed at Invitae indicates that this missense variant is expected to disrupt CLN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Val330 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9311735, 19132115, 22013180). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001729444	SCV001977422	likely pathogenic	Neuronal ceroid lipofuscinosis 3	2021-08-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816316	SCV005069885	likely pathogenic	Retinal dystrophy	2021-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004975317	SCV005561944	likely pathogenic	Inborn genetic diseases	2024-11-05	criteria provided, single submitter	clinical testing	The c.988G>A (p.V330I) alteration is located in exon 14 (coding exon 13) of the CLN3 gene. This alteration results from a G to A substitution at nucleotide position 988, causing the valine (V) at amino acid position 330 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/280370) total alleles studied. The highest observed frequency was 0.008% (2/24804) of European (Finnish) alleles. This variant has been identified in conjunction with other CLN3 variants in individuals with features consistent with CLN3-related disorders (Ku, 2017; external communication). This amino acid position is highly conserved in available vertebrate species. In an assay testing CLN3 function, this variant showed a functionally abnormal result (Scotto Rosato, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001729444	SCV005646529	likely pathogenic	Neuronal ceroid lipofuscinosis 3	2024-01-02	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504655	SCV000599195	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Myriad Genetics, Inc.	RCV001729444	SCV002060110	uncertain significance	Neuronal ceroid lipofuscinosis 3	2021-11-10	flagged submission	clinical testing	NM_001042432.1(CLN3):c.988G>A(V330I) is a missense variant classified as a variant of uncertain significance in the context of CLN3-related neuronal ceroid lipofuscinosis. V330I has been observed in cases with relevant disease (PMID: 28542676). Functional assessments of this variant are not available in the literature. V330I has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_001042432.1(CLN3):c.988G>A(V330I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.