Submissions for variant NM_138387.4(G6PC3):c.757C>T (p.Arg253Cys)

gnomAD frequency: 0.00002  dbSNP: rs765927570

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234589	SCV001407243	uncertain significance	Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 253 of the G6PC3 protein (p.Arg253Cys). 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 missense change has been observed in individual(s) with non-syndromic severe congenital neutropenia (PMID: 23298686). ClinVar contains an entry for this variant (Variation ID: 960968). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg253 amino acid residue in G6PC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19118303, 20717171). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001311132	SCV001501188	likely pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing