Submissions for variant NM_152564.5(VPS13B):c.2471C>T (p.Ser824Phe)

gnomAD frequency: 0.00016  dbSNP: rs145419141

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726533	SCV000345300	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000283079	SCV000597879	uncertain significance	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Invitae	RCV000792079	SCV000931352	uncertain significance	Cohen syndrome	2022-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 824 of the VPS13B protein (p.Ser824Phe). This variant is present in population databases (rs145419141, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 290694). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000726533	SCV001245918	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000792079	SCV001806347	uncertain significance	Cohen syndrome	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450831	SCV002737458	uncertain significance	Inborn genetic diseases	2021-09-09	criteria provided, single submitter	clinical testing	The c.2471C>T (p.S824F) alteration is located in exon 17 (coding exon 16) of the VPS13B gene. This alteration results from a C to T substitution at nucleotide position 2471, causing the serine (S) at amino acid position 824 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000792079	SCV002784426	uncertain significance	Cohen syndrome	2022-02-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003391056	SCV004110838	uncertain significance	VPS13B-related disorder	2024-02-27	criteria provided, single submitter	clinical testing	The VPS13B c.2471C>T variant is predicted to result in the amino acid substitution p.Ser824Phe. This variant was reported in the homozygous state in an individual with late‑onset hemophagocytic lymphohistiocytosis; however, this variant was not considered as the primary cause of disease (Zondag et al. 2022. PubMed ID: 35870028). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, a different variant impacting the same amino acid (p.Ser824Ala) was found in the homozygous state in a patient with a mild version of Cohen syndrome; however, it was reported (phase not indicated) in an unaffected family member (Family AU-17800, Yu et al. 2013. PubMed ID: 23352163). At this time, the clinical significance of the c.2471C>T (p.Ser824Phe) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000792079	SCV001456252	likely benign	Cohen syndrome	2020-04-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726533	SCV001550611	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VPS13B p.Ser824Phe variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs145419141) and ClinVar (classified as a VUS by Invitae, EGL Genetics and Genetic Services Laboratory at the University of Chicago). The variant was also identified in control databases in 42 of 282596 chromosomes at a frequency of 0.000149 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 29 of 129016 chromosomes (freq: 0.000225), Latino in 7 of 35434 chromosomes (freq: 0.000198), South Asian in 5 of 30608 chromosomes (freq: 0.000163) and Other in 1 of 7216 chromosomes (freq: 0.000139), but was not observed in the African, Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Ser824 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000726533	SCV001799349	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726533	SCV001976268	uncertain significance	not provided		no assertion criteria provided	clinical testing