ClinVar Miner

Submissions for variant NM_000081.4(LYST):c.6737T>G (p.Leu2246Arg)

gnomAD frequency: 0.00004  dbSNP: rs200231136
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489794 SCV000577213 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing The L2246R variant in the LYST gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L2246R variant is observed in 1/66666 (0.0015%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The L2246R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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 L2246R as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001214038 SCV001385701 uncertain significance Chédiak-Higashi syndrome 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2246 of the LYST protein (p.Leu2246Arg). This variant is present in population databases (rs200231136, gnomAD 0.004%). 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: 426698). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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.
Ambry Genetics RCV002526028 SCV003686166 uncertain significance Inborn genetic diseases 2022-03-10 criteria provided, single submitter clinical testing The c.6737T>G (p.L2246R) alteration is located in exon 23 (coding exon 21) of the LYST gene. This alteration results from a T to G substitution at nucleotide position 6737, causing the leucine (L) at amino acid position 2246 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003409675 SCV004109852 uncertain significance LYST-related disorder 2023-03-28 criteria provided, single submitter clinical testing The LYST c.6737T>G variant is predicted to result in the amino acid substitution p.Leu2246Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-235922416-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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