Submissions for variant NM_000081.4(LYST):c.3083C>G (p.Ser1028Cys)

gnomAD frequency: 0.00049  dbSNP: rs150636017

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000301818	SCV000355772	uncertain significance	Chédiak-Higashi syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000493084	SCV000582251	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Reported in patients with juvenile idiopathic arthritis, however segregation and detailed clinical information was not provided (Meng et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33408077)
Fulgent Genetics, Fulgent Genetics	RCV000301818	SCV000896290	uncertain significance	Chédiak-Higashi syndrome	2022-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000301818	SCV000937081	uncertain significance	Chédiak-Higashi syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1028 of the LYST protein (p.Ser1028Cys). This variant is present in population databases (rs150636017, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 296408). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000493084	SCV001715410	uncertain significance	not provided	2020-06-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262933	SCV002543621	uncertain significance	Autoinflammatory syndrome	2020-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522120	SCV003564850	uncertain significance	Inborn genetic diseases	2022-02-28	criteria provided, single submitter	clinical testing	The c.3083C>G (p.S1028C) alteration is located in exon 6 (coding exon 4) of the LYST gene. This alteration results from a C to G substitution at nucleotide position 3083, causing the serine (S) at amino acid position 1028 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000301818	SCV003815250	uncertain significance	Chédiak-Higashi syndrome	2019-10-03	criteria provided, single submitter	clinical testing