Submissions for variant NM_000081.4(LYST):c.4705A>C (p.Asn1569His)

gnomAD frequency: 0.00004  dbSNP: rs767687843

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000309417	SCV000355755	uncertain significance	Chédiak-Higashi syndrome	2018-01-13	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.
Invitae	RCV000309417	SCV000750123	uncertain significance	Chédiak-Higashi syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1569 of the LYST protein (p.Asn1569His). This variant is present in population databases (rs767687843, gnomAD 0.01%). 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: 296395). 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.
Fulgent Genetics, Fulgent Genetics	RCV000309417	SCV000894772	uncertain significance	Chédiak-Higashi syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788549	SCV000927701	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000788549	SCV001823541	likely benign	not provided	2021-01-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262932	SCV002543635	uncertain significance	Autoinflammatory syndrome	2021-02-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940114	SCV004754535	uncertain significance	LYST-related disorder	2023-10-26	criteria provided, single submitter	clinical testing	The LYST c.4705A>C variant is predicted to result in the amino acid substitution p.Asn1569His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-235950657-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004021440	SCV004900861	uncertain significance	Inborn genetic diseases	2021-08-02	criteria provided, single submitter	clinical testing	The c.4705A>C (p.N1569H) alteration is located in exon 14 (coding exon 12) of the LYST gene. This alteration results from a A to C substitution at nucleotide position 4705, causing the asparagine (N) at amino acid position 1569 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.