ClinVar Miner

Submissions for variant NM_001301365.1(LYST):c.6454A>C (p.Ser2152Arg)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000380641 SCV000355742 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.
Broad Institute Rare Disease Group,Broad Institute RCV000380641 SCV001164394 uncertain significance Chédiak-Higashi syndrome 2018-12-03 criteria provided, single submitter research The heterozygous p.Ser2152Arg variant in LYST was identified by our study in the compound heterozygous state, with another VUS, in one individual with Chediak-Higashi syndrome. The p.Ser2152Arg variant in LYST has not been previously reported in individuals with Chediak-Higashi syndrome but has been identified in 0.01664% (4/24032) of African chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs201317160). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 296386). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ser2152Arg variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
Invitae RCV000380641 SCV001212895 uncertain significance Chédiak-Higashi syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 2152 of the LYST protein (p.Ser2152Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs201317160, ExAC 0.03%). This variant has not been reported in the literature in individuals with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 296386). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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