Submissions for variant NM_005263.5(GFI1):c.1126G>A (p.Ala376Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003406236	SCV004108281	uncertain significance	GFI1-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The GFI1 c.1126G>A variant is predicted to result in the amino acid substitution p.Ala376Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-92941729-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003619844	SCV004484948	uncertain significance	Neutropenia, severe congenital, 2, autosomal dominant	2022-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 376 of the GFI1 protein (p.Ala376Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GFI1-related conditions. 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 GFI1 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.