Submissions for variant NM_000081.4(LYST):c.3683A>G (p.Asn1228Ser)

gnomAD frequency: 0.00171  dbSNP: rs145553827

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788254	SCV000927305	uncertain significance	not provided	2017-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV001080279	SCV001016084	likely benign	Chédiak-Higashi syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001080279	SCV001468425	uncertain significance	Chédiak-Higashi syndrome	2021-03-30	criteria provided, single submitter	clinical testing	LYST NM_000081.3 exon 8 p.Asn1228Ser (c.3683A>G): This variant has not been reported in the literature but is present in 0.5% (127/24970) of African alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/1-235966237-T-C). This variant is present in ClinVar (Variation ID:636426). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000788254	SCV001791834	likely benign	not provided	2020-01-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263976	SCV002543627	uncertain significance	Autoinflammatory syndrome	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509536	SCV002819688	uncertain significance	not specified	2022-12-20	criteria provided, single submitter	clinical testing	Variant summary: LYST c.3683A>G (p.Asn1228Ser) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 250934 control chromosomes, predominantly at a frequency of 0.0052 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes suggesting a benign role for this variant. To our knowledge, c.3683A>G has not been reported in the literature in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classsifed the variant as VUS (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002535771	SCV003610126	likely benign	Inborn genetic diseases	2022-08-17	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.
PreventionGenetics, part of Exact Sciences	RCV003947980	SCV004762775	likely benign	LYST-related disorder	2019-10-02	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).