Submissions for variant NM_000081.4(LYST):c.6460G>A (p.Asp2154Asn)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629189	SCV000750105	uncertain significance	Chédiak-Higashi syndrome	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2154 of the LYST protein (p.Asp2154Asn). This variant is present in population databases (rs746634900, 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: 525147). 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.
Illumina Laboratory Services, Illumina	RCV000629189	SCV001252719	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.
Revvity Omics, Revvity	RCV000629189	SCV003815225	uncertain significance	Chédiak-Higashi syndrome	2019-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689815	SCV005184889	uncertain significance	not specified	2024-05-10	criteria provided, single submitter	clinical testing	Variant summary: LYST c.6460G>A (p.Asp2154Asn) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251196 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.6460G>A in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 525147). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791638	SCV005411542	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	BP4
Ambry Genetics	RCV004985023	SCV005618967	uncertain significance	Inborn genetic diseases	2024-10-01	criteria provided, single submitter	clinical testing	The c.6460G>A (p.D2154N) alteration is located in exon 23 (coding exon 21) of the LYST gene. This alteration results from a G to A substitution at nucleotide position 6460, causing the aspartic acid (D) at amino acid position 2154 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.