Submissions for variant NM_000081.4(LYST):c.3208A>G (p.Ile1070Val)

gnomAD frequency: 0.00043  dbSNP: rs150321124

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052923	SCV001217158	uncertain significance	Chédiak-Higashi syndrome	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1070 of the LYST protein (p.Ile1070Val). This variant is present in population databases (rs150321124, gnomAD 0.1%). 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: 849040). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV001052923	SCV001258776	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.
GeneDx	RCV001356349	SCV001992688	uncertain significance	not provided	2019-06-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001819773	SCV002070693	uncertain significance	not specified	2019-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003160415	SCV003873741	uncertain significance	Inborn genetic diseases	2023-03-06	criteria provided, single submitter	clinical testing	The c.3208A>G (p.I1070V) alteration is located in exon 6 (coding exon 4) of the LYST gene. This alteration results from a A to G substitution at nucleotide position 3208, causing the isoleucine (I) at amino acid position 1070 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356349	SCV001551494	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LYST p.I1070V variant was not identified in the literature but was identified in dbSNP (ID: rs150321124) and ClinVar (classified as uncertain significance by Invitae and Illumina for Chédiak-Higashi syndrome). The variant was identified in control databases in 52 of 282286 chromosomes at a frequency of 0.0001842 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I1070 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.