Submissions for variant NM_000081.4(LYST):c.2363+4T>C

gnomAD frequency: 0.00252  dbSNP: rs201398337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194897	SCV000247874	uncertain significance	not specified	2015-06-16	criteria provided, single submitter	clinical testing
Invitae	RCV000876549	SCV001019139	benign	Chédiak-Higashi syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000876549	SCV001468424	uncertain significance	Chédiak-Higashi syndrome	2021-12-08	criteria provided, single submitter	clinical testing	LYST NM_000081.3 exon 5 c.2363+4T>C: This variant has not been reported in the literature but is present in 0.2% (270/128716) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235971751-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:211407). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV002056993	SCV002496995	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LYST: BP4, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262786	SCV002543301	likely benign	Autoinflammatory syndrome	2018-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517948	SCV003549354	likely benign	Inborn genetic diseases	2022-03-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194897	SCV004038733	benign	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: LYST c.2363+4T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing, and 1/4 predict the variant strengthens a cryptic 5' splice donor site 4nt into intron 5. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 281942 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2363+4T>C in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.