Submissions for variant NM_000081.4(LYST):c.2465C>T (p.Thr822Ile)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004899	SCV001164395	uncertain significance	Chédiak-Higashi syndrome	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Thr822Ile variant in LYST was identified by our study in the compound heterozygous state, with another VUS, in one individual with Chediak-Higashi syndrome. The p.Thr822Ile variant in LYST has not been previously reported in individuals with Chediak-Higashi syndrome but has been identified in 0.01665% (4/24028) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199746236). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr822Ile variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
Invitae	RCV001004899	SCV001207043	uncertain significance	Chédiak-Higashi syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 822 of the LYST protein (p.Thr822Ile). This variant is present in population databases (rs199746236, gnomAD 0.02%). 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: 813928). 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 LYST 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.
Illumina Laboratory Services, Illumina	RCV001004899	SCV001256727	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.
Ambry Genetics	RCV002549263	SCV003551456	uncertain significance	Inborn genetic diseases	2021-07-16	criteria provided, single submitter	clinical testing	The c.2465C>T (p.T822I) alteration is located in exon 6 (coding exon 4) of the LYST gene. This alteration results from a C to T substitution at nucleotide position 2465, causing the threonine (T) at amino acid position 822 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001004899	SCV003815321	uncertain significance	Chédiak-Higashi syndrome	2021-09-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411948	SCV004114405	uncertain significance	LYST-related condition	2023-04-26	criteria provided, single submitter	clinical testing	The LYST c.2465C>T variant is predicted to result in the amino acid substitution p.Thr822Ile. This variant has been reported in an individual with multiple sclerosis (Jafarpour et al. 2022. PubMed ID: 35960392). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-235969971-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.