Submissions for variant NM_003764.4(STX11):c.173T>C (p.Leu58Pro)

gnomAD frequency: 0.00001  dbSNP: rs431905512

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269565	SCV001449641	pathogenic	not provided	2016-04-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083252	SCV001577802	pathogenic	Familial hemophagocytic lymphohistiocytosis 4	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 58 of the STX11 protein (p.Leu58Pro). This variant is present in population databases (rs431905512, gnomAD 0.007%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 24459464, 26004995; Invitae). ClinVar contains an entry for this variant (Variation ID: 97001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STX11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STX11 function (PMID: 24459464). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000083252	SCV004806140	pathogenic	Familial hemophagocytic lymphohistiocytosis 4	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700400	SCV005204378	pathogenic	Familial hemophagocytic lymphohistiocytosis	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: STX11 c.173T>C (p.Leu58Pro) results in a non-conservative amino acid change located in the Syntaxin, N-terminal domain (IPR006011) of 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 8e-06 in 250684 control chromosomes. c.173T>C has been reported in the literature in multiple homozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Mller_2013, Khan_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced cytotoxic activity and degranulation capacity in mouse CD8+ T cells (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 26004995, 24459464, 36706356). ClinVar contains an entry for this variant (Variation ID: 97001). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000083252	SCV000115331	pathogenic	Familial hemophagocytic lymphohistiocytosis 4	2014-01-14	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000083252	SCV001133261	uncertain significance	Familial hemophagocytic lymphohistiocytosis 4	2019-09-26	no assertion criteria provided	clinical testing