Submissions for variant NM_000081.4(LYST):c.10235G>A (p.Arg3412His)

gnomAD frequency: 0.00073  dbSNP: rs148409403

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629197	SCV000750114	uncertain significance	Chédiak-Higashi syndrome	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3412 of the LYST protein (p.Arg3412His). This variant is present in population databases (rs148409403, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary immunodeficiency (PMID: 27872624). ClinVar contains an entry for this variant (Variation ID: 525155). 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 LYST protein function. 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.
Eurofins Ntd Llc (ga)	RCV000727994	SCV000855511	uncertain significance	not provided	2017-07-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000629197	SCV001258358	uncertain significance	Chédiak-Higashi syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263843	SCV002543599	uncertain significance	Autoinflammatory syndrome	2017-07-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002528826	SCV003682539	uncertain significance	Inborn genetic diseases	2020-11-18	criteria provided, single submitter	clinical testing	The c.10235G>A (p.R3412H) alteration is located in exon 45 (coding exon 43) of the LYST gene. This alteration results from a G to A substitution at nucleotide position 10235, causing the arginine (R) at amino acid position 3412 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the LYST c.10235G>A alteration was observed in 0.07% (194/282734) of total alleles studied, with a frequency of 0.2% (21/10364) in the Ashkenazi Jewish subpopulation. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.R3412H alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000629197	SCV003815261	uncertain significance	Chédiak-Higashi syndrome	2020-03-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411488	SCV004115945	uncertain significance	LYST-related disorder	2023-03-01	criteria provided, single submitter	clinical testing	The LYST c.10235G>A variant is predicted to result in the amino acid substitution p.Arg3412His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-235866186-C-T). 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.