Submissions for variant NM_000760.4(CSF3R):c.355G>A (p.Ala119Thr)

gnomAD frequency: 0.00089  dbSNP: rs142999683

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685892	SCV000813392	uncertain significance	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency	2024-12-24	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 119 of the CSF3R protein (p.Ala119Thr). This variant is present in population databases (rs142999683, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hematological malignancies (PMID: 33108454). ClinVar contains an entry for this variant (Variation ID: 566149). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CSF3R protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CSF3R function (PMID: 33108454). 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.
Genetic Services Laboratory, University of Chicago	RCV001816697	SCV002067113	uncertain significance	not specified	2021-09-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CSF3R gene demonstrated a sequence change, c.355G>A, in exon 4 that results in an amino acid change, p.Ala119Thr. This sequence change has been described in the gnomAD database with a frequency of 0.12% in the Finnish European subpopulation (dbSNP rs142999683). This sequence change has also been previously described in one individual with multiple myeloma and one individual with acute lymphoblastic leukemia (PMID: 33108454). In addition, this sequence change has been observed in several samples tested in our laboratory with other indications besides cancer. The p.Ala119Thr change affects a highly conserved amino acid residue located in the Ig-like domain of the CSF3R protein. Functional studies show p.Ala119Thr disrupts G-CSF-induced CSF3R activation (PMID: 33108454). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala119Thr substitution. Due to the above information we are currently interpreting the p.Ala119Thr variant as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV002261173	SCV002542008	uncertain significance	not provided	2021-07-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485593	SCV002777885	uncertain significance	Hereditary neutrophilia; Autosomal recessive severe congenital neutropenia due to CSF3R deficiency	2022-04-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV002261173	SCV005186608	uncertain significance	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV002261173	SCV005330796	uncertain significance	not provided	2025-01-01	criteria provided, single submitter	clinical testing