Submissions for variant NM_015378.4(VPS13D):c.11459A>T (p.Asn3820Ile)

gnomAD frequency: 0.00043  dbSNP: rs142270656

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095714	SCV001251552	uncertain significance	Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	2020-01-10	criteria provided, single submitter	clinical testing	The VPS13D c.11459A>T (p.Asn3820Ile) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.000605 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Asn3820Ile variant is classified as variant of unknown significance for VPS13D-related movement disorder.
GeneDx	RCV001726428	SCV001995950	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001726428	SCV002146558	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3820 of the VPS13D protein (p.Asn3820Ile). This variant is present in population databases (rs142270656, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with VPS13D-related conditions. ClinVar contains an entry for this variant (Variation ID: 873479). 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 not expected to disrupt VPS13D protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV004032001	SCV004980825	uncertain significance	Inborn genetic diseases	2021-09-17	criteria provided, single submitter	clinical testing	The c.11459A>T (p.N3820I) alteration is located in exon 59 (coding exon 58) of the VPS13D gene. This alteration results from a A to T substitution at nucleotide position 11459, causing the asparagine (N) at amino acid position 3820 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726428	SCV001962860	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726428	SCV001967698	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004756169	SCV005345332	uncertain significance	VPS13D-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The VPS13D c.11459A>T variant is predicted to result in the amino acid substitution p.Asn3820Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.