Submissions for variant NM_033305.3(VPS13A):c.5246C>T (p.Ser1749Leu)

gnomAD frequency: 0.00002  dbSNP: rs781398633

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001357634	SCV001994723	uncertain significance	not provided	2019-03-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001357634	SCV002220692	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 1749 of the VPS13A protein (p.Ser1749Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs781398633, ExAC 0.02%). This variant has not been reported in the literature in individuals with VPS13A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV002476639	SCV002781580	uncertain significance	Chorea-acanthocytosis	2021-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004968113	SCV005531659	likely benign	Inborn genetic diseases	2024-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357634	SCV001553158	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VPS13A p.Ser1749Leu variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs781398633) and in control databases in 23 of 280014 chromosomes at a frequency of 0.000082 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 14 of 35358 chromosomes (freq: 0.000396), Other in 2 of 7176 chromosomes (freq: 0.000279), Ashkenazi Jewish in 2 of 10338 chromosomes (freq: 0.000194), African in 1 of 24920 chromosomes (freq: 0.00004) and European (non-Finnish) in 4 of 126584 chromosomes (freq: 0.000032); it was not observed in the East Asian, European (Finnish), and South Asian populations. The p.Ser1749 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.