Submissions for variant NM_000081.4(LYST):c.2570C>G (p.Ser857Cys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001206360	SCV001377666	uncertain significance	Chédiak-Higashi syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 857 of the LYST protein (p.Ser857Cys). This variant is present in population databases (rs144261004, gnomAD 0.004%). This missense change has been observed in individual(s) with Chediak-Higashi syndrome (PMID: 21878672). ClinVar contains an entry for this variant (Variation ID: 937365). 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. 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.
Revvity Omics, Revvity	RCV001206360	SCV003815310	uncertain significance	Chédiak-Higashi syndrome	2019-12-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323818	SCV004028938	uncertain significance	not specified	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: LYST c.2570C>G (p.Ser857Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251050 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2570C>G has been reported in the literature in an individual affected with Chediak-Higashi Syndrome, however, this individual was also homozygous for LYST c.9930delT; p.Phe3310LeufsX36 (example: Jessen_2011) . These report(s) do not provide unequivocal conclusions about association of the variant with Chediak-Higashi Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21878672). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.