ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.988G>A (p.Val330Ile) (rs386833744)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187016 SCV000240589 pathogenic not provided 2013-05-23 criteria provided, single submitter clinical testing p.Val330Ile (GTC>ATC): c.988 G>A in exon 14 of the CLN3 gene (NM_001042432.1). The Val330Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Val330Ile is a conservative amino acid substitution as both Valine and Isoleucine are neutral, non-polar amino acids; however, this substitution occurs at a highly conserved position in the loop between the 5th and 6th transmembrane segments of the CLN3 protein. Multiple in silico algorithms predict Val330Ile may be damaging to the structure/function of the protein. Therefore, Val330Ile is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae RCV000812919 SCV000953249 uncertain significance Neuronal ceroid lipofuscinosis 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 330 of the CLN3 protein (p.Val330Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs386833744, ExAC 0.02%). This variant has been observed in an individual with CLN3-associated nonsyndromic retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 205095). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504655 SCV000599195 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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