Submissions for variant NM_001364905.1(LRBA):c.1771T>C (p.Tyr591His)

gnomAD frequency: 0.00038  dbSNP: rs138890467

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788175	SCV000927205	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing
Invitae	RCV000808184	SCV000948279	uncertain significance	Combined immunodeficiency due to LRBA deficiency	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 591 of the LRBA protein (p.Tyr591His). This variant is present in population databases (rs138890467, gnomAD 0.04%). 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: 636373). 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 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000808184	SCV001711933	uncertain significance	Combined immunodeficiency due to LRBA deficiency	2021-05-18	criteria provided, single submitter	clinical testing	This LRBA variant (rs138890467) is rare (<0.1%) in a large population dataset (gnomAD: 57/276114 total alleles, 0.02%, no homozygotes) and has an entry in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the tyrosine residue at this position is strongly conserved across all vertebrate species assessed. This variant is not predicted to affect normal exon 14 splicing, although this has not been confirmed experimentally to our knowledge. This variant alone is not expected to cause CVID. Due to insufficient evidence we consider the clinical significance of c.1771T>C to be uncertain at this time.
CeGaT Center for Human Genetics Tuebingen	RCV000788175	SCV001746808	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000788175	SCV001963128	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000788175	SCV001969715	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000788175	SCV002035299	uncertain significance	not provided		no assertion criteria provided	clinical testing