Submissions for variant NM_000081.4(LYST):c.7862T>C (p.Met2621Thr)

gnomAD frequency: 0.00006  dbSNP: rs368500877

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702332	SCV000831184	uncertain significance	Chédiak-Higashi syndrome	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2621 of the LYST protein (p.Met2621Thr). This variant is present in population databases (rs368500877, 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: 579125). 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. 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)	RCV000728210	SCV000855755	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000728210	SCV001246387	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000702332	SCV001252606	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	RCV002536355	SCV003760106	uncertain significance	Inborn genetic diseases	2022-07-13	criteria provided, single submitter	clinical testing	The c.7862T>C (p.M2621T) alteration is located in exon 29 (coding exon 27) of the LYST gene. This alteration results from a T to C substitution at nucleotide position 7862, causing the methionine (M) at amino acid position 2621 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230577	SCV003928619	uncertain significance	not specified	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: LYST c.7862T>C (p.Met2621Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251334 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (7.6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7862T>C in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, and four as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.