ClinVar Miner

Submissions for variant NM_000081.4(LYST):c.4336C>T (p.Arg1446Trp)

gnomAD frequency: 0.00010  dbSNP: rs200276917
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001232786 SCV001405354 uncertain significance Chédiak-Higashi syndrome 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1446 of the LYST protein (p.Arg1446Trp). This variant is present in population databases (rs200276917, gnomAD 0.02%). 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: 959432). 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.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001644955 SCV001519289 uncertain significance Spastic ataxia 2021-01-04 criteria provided, single submitter research
Revvity Omics, Revvity RCV001232786 SCV003815198 uncertain significance Chédiak-Higashi syndrome 2019-06-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354786 SCV001549484 uncertain significance not provided no assertion criteria provided clinical testing The LYST p.Arg1446Trp variant was not identified in the literature nor was it identified in the Clinvar, Clinvitae, COSMIC and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs200276917) and in control databases in 24 of 282522 chromosomes at a frequency of 0.000085 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7216 chromosomes (freq: 0.000416), Latino in 5 of 35438 chromosomes (freq: 0.000141), African in 3 of 24966 chromosomes (freq: 0.00012) and European (non-Finnish) in 13 of 128892 chromosomes (freq: 0.000101), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The c.4336C>T variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg1446 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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.

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