Submissions for variant NM_000081.4(LYST):c.6710A>C (p.Gln2237Pro)

gnomAD frequency: 0.00148  dbSNP: rs138443479

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192717	SCV000247878	uncertain significance	not specified	2015-06-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329381	SCV000355738	uncertain significance	Chédiak-Higashi syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000329381	SCV000750166	likely 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	RCV000329381	SCV001468423	uncertain significance	Chédiak-Higashi syndrome	2021-12-08	criteria provided, single submitter	clinical testing	LYST NM_000081.3 exon23 p.Gln2237Pro (c.6710A>C): This variant has not been reported in the literature but is present in 0.2% (285/128512) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235922443-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:211411). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262789	SCV002543367	likely benign	Autoinflammatory syndrome	2018-09-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001354479	SCV002585190	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LYST: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192717	SCV004038732	likely benign	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: LYST c.6710A>C (p.Gln2237Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 282064 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 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. c.6710A>C has been reported in the literature in an individual with suspected Inherited Bleeding Disorders without evidence for causality (Leinoe_2017). 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: 28748566). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003917758	SCV004729627	likely benign	LYST-related disorder	2022-06-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004020323	SCV004900869	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354479	SCV001549106	likely benign	not provided		no assertion criteria provided	clinical testing	The LYST p.Gln2237Pro variant was not identified in the literature nor was it identified in Cosmic. The variant was found in dbSNP (ID: rs138443479), LOVD 3.0 and in ClinVar (classified as Likely Benign by Invitae and as a VUS by Genetics Services Laboratory (University of Chicago) and Illumina for Chédiak-Higashi syndrome). The variant was identified in control databases in 430 of 282064 chromosomes (2 homozygous) at a frequency of 0.001524 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 49 of 10346 chromosomes (freq: 0.004736), European (Finnish) in 71 of 25108 chromosomes (freq: 0.002828), European (non-Finnish) in 285 of 128512 chromosomes (freq: 0.002218), Other in 11 of 7202 chromosomes (freq: 0.001527), Latino in 10 of 35378 chromosomes (freq: 0.000283) and African in 4 of 24966 chromosomes (freq: 0.00016), while the variant was not observed in the East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer); SpliceSiteFinder-like and MaxEntScan, predict the shift of a 3' splice site from c.6711 to c.6716. However, this information is not very predictive of pathogenicity. The p.Gln2237 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is also not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would suggest a more benign role for this variant. This variant is classified as likely benign.