ClinVar Miner

Submissions for variant NM_001301365.1(LYST):c.11354G>A (p.Arg3785His) (rs370173269)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523238 SCV000619862 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing The R3785H variant in the LYST gene has not been published in a peer reviewed journal as a pathogenic variant, nor as a benign variant, to our knowledge. However, in an abstract by Kunz et al. (2013), an individual with hemophagocytic lymphohistiocytosis and partial albinism was reported to have the R3785H variant in trans with another missense variant in the LYST gene identified via whole exome sequencing, although no lysosomal granules were present in this individual's blood cells. The R3785H variant is observed in 1/8,652 (0.011%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al., 2016). The R3785H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R3785H as a variant of uncertain significance.
Invitae RCV000696852 SCV000825432 uncertain significance Chédiak-Higashi syndrome 2018-05-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 3785 of the LYST protein (p.Arg3785His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs370173269, ExAC 0.01%). This variant has not been reported in the literature in individuals with LYST-related disease. ClinVar contains an entry for this variant (Variation ID: 451194). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 Clinical Services Laboratory,Illumina RCV000696852 SCV001252397 uncertain significance Chédiak-Higashi syndrome 2017-04-28 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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