Submissions for variant NM_000081.4(LYST):c.8913T>G (p.Asn2971Lys)

gnomAD frequency: 0.00276  dbSNP: rs34702903

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001027832	SCV000750141	likely benign	Chédiak-Higashi syndrome	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000629223	SCV001147719	uncertain significance	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027832	SCV001190452	likely benign	Chédiak-Higashi syndrome	2022-08-30	criteria provided, single submitter	clinical testing	LYST NM_000081.3 exon 35 p.Asn2971Lys (c.8913T>G): This variant has been reported in the literature in at least 1 individual with cerebellar ataxia (Coutelier 2018 PMID:29482223). This variant is present in 0.4% (580/129120) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235894366-A-C). This variant is present in ClinVar (Variation ID:525179). Evolutionary conservation suggests that this variant may impact the protein; 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.
Illumina Laboratory Services, Illumina	RCV001027832	SCV001254392	uncertain significance	Chédiak-Higashi syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000629223	SCV001713140	uncertain significance	not provided	2019-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000629223	SCV001782685	likely benign	not provided	2019-11-27	criteria provided, single submitter	clinical testing	Identified as a single heterozygous variant in two individuals with fatal H1N1 influenza and identified with another LYST variant in another individual with cerebellar ataxia, but limited phenotypic information was provided on these individuals (Schulert et al., 2016; Coutelier et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29482223, 26597256)
Genetic Services Laboratory, University of Chicago	RCV001821769	SCV002065497	uncertain significance	not specified	2021-06-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263846	SCV002543675	uncertain significance	Autoinflammatory syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821769	SCV004223630	uncertain significance	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: LYST c.8913T>G (p.Asn2971Lys) 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 0.0024 in 251384 control chromosomes. The observed variant frequency is approximately 2.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011), suggesting that the variant is benign. c.8913T>G has been reported in the literature in settings of whole exome or multigene panel testing in individuals affected with clinical features that have been reported in Chediak-Higashi Syndrome, including cerebellar ataxia, reported as a VUS with compound heterozygous genotype (e.g.Coutelier_2018), fatal H1N1, reported as a VUS in a heterozygous genotype (e.g. Schulert_2016), unspecified inherited bleeding disorder with unspecified genotype (e.g. Leinoe_2017), and unclassified neuroinflammatory disease with isolated incidence of hemiplegia and ataxia as a compound heterozygous genotype with variants in multiple neuroinflammatory genes (e.g.McCreary_2019). 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 publications have been ascertained in the context of this evaluation (PMID: 29482223, 28748566, 31664448, 26597256). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003928044	SCV004744587	likely benign	LYST-related disorder	2021-05-12	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).