Submissions for variant NM_000081.4(LYST):c.8806G>A (p.Val2936Ile)

gnomAD frequency: 0.00052  dbSNP: rs2753327

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629187	SCV000750103	uncertain significance	Chédiak-Higashi syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2936 of the LYST protein (p.Val2936Ile). This variant is present in population databases (rs2753327, gnomAD 0.1%), 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: 525145). 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.
GeneDx	RCV000658240	SCV000780011	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Observed in a patient with primary platelet secretion defect; this individual also harbored variants in other possible causative genes (Gorski et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30819905, 18485661, 27535533)
Fulgent Genetics, Fulgent Genetics	RCV000629187	SCV000894771	uncertain significance	Chédiak-Higashi syndrome	2021-08-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000629187	SCV001256311	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000629187	SCV002495830	uncertain significance	Chédiak-Higashi syndrome	2021-05-11	criteria provided, single submitter	clinical testing	LYST NM_000081.3 exon 35 p.Val2936Ile (c.8806G>A): This variant has not been reported in the literature but is present in 0.08% (57/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235731173-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:525145). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263841	SCV002543673	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002528824	SCV003549375	uncertain significance	Inborn genetic diseases	2021-06-06	criteria provided, single submitter	clinical testing	(Gorski, 2019; Leinoe, 2017) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000629187	SCV003815320	uncertain significance	Chédiak-Higashi syndrome	2019-11-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658240	SCV004033008	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	LYST: BP4