ClinVar Miner

Submissions for variant NM_001364905.1(LRBA):c.7937T>G (p.Ile2646Ser)

dbSNP: rs199469663
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000029134 SCV001403574 pathogenic Combined immunodeficiency due to LRBA deficiency 2023-05-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LRBA function (PMID: 22608502, 25931386). 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. ClinVar contains an entry for this variant (Variation ID: 35455). This variant is also known as c.7937T>G: p.I2646S. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2657 of the LRBA protein (p.Ile2657Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset immune deficiency and autoimmunity (PMID: 22608502, 25931386, 28197149). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals.
Neuberg Centre For Genomic Medicine, NCGM RCV000029134 SCV004048174 pathogenic Combined immunodeficiency due to LRBA deficiency criteria provided, single submitter clinical testing The variant c.7970T>G (p.Ile2657Ser) in LRBA gene has been previously reported in individuals with early-onset immune deficiency and autoimmunity (LopezHerrera G et al, Revel-Vilk S et al). This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ile at position 2657 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. This sequence change replaces isoleucine with serine at codon 2657 of the LRBA protein (p.Ile2657Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. The residue is conserved across species. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ile2657Ser in LRBA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Ile2657Ser variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as pathogenic.
OMIM RCV000029134 SCV000050584 pathogenic Combined immunodeficiency due to LRBA deficiency 2012-06-08 no assertion criteria provided literature only

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