Submissions for variant NM_001364905.1(LRBA):c.3499A>G (p.Thr1167Ala)

gnomAD frequency: 0.00026  dbSNP: rs146297781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202792	SCV000257835	uncertain significance	not specified	2015-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814079	SCV000954476	uncertain significance	Combined immunodeficiency due to LRBA deficiency	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1167 of the LRBA protein (p.Thr1167Ala). This variant is present in population databases (rs146297781, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with LRBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 218543). 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 not expected to disrupt LRBA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002517346	SCV003651760	uncertain significance	Inborn genetic diseases	2021-09-16	criteria provided, single submitter	clinical testing	The c.3499A>G (p.T1167A) alteration is located in exon 23 (coding exon 22) of the LRBA gene. This alteration results from a A to G substitution at nucleotide position 3499, causing the threonine (T) at amino acid position 1167 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480551	SCV004227034	uncertain significance	not provided	2022-03-23	criteria provided, single submitter	clinical testing	BP4
3billion	RCV000814079	SCV005328852	likely benign	Combined immunodeficiency due to LRBA deficiency	2024-09-20	criteria provided, single submitter	clinical testing	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000814079	SCV005689107	uncertain significance	Combined immunodeficiency due to LRBA deficiency	2025-02-05	criteria provided, single submitter	clinical testing	The LRBA c.3499A>G (p.Thr1167Ala) missense change has a maximum subpopulation frequency of 0.06% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals LRBA-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.