Submissions for variant NM_006361.6(HOXB13):c.610G>A (p.Gly204Arg)

gnomAD frequency: 0.00003  dbSNP: rs1014715541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567281	SCV000669452	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing	The c.610G>A (p.G204R) alteration is located in exon 2 (coding exon 2) of the HOXB13 gene. This alteration results from a G to A substitution at nucleotide position 610, causing the glycine (G) at amino acid position 204 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045832	SCV001209706	uncertain significance	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 204 of the HOXB13 protein (p.Gly204Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HOXB13-related conditions. ClinVar contains an entry for this variant (Variation ID: 483477). 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 not expected to disrupt HOXB13 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001045832	SCV001772536	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000567281	SCV002536968	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001045832	SCV005625206	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The HOXB13 c.610G>A (p.Gly204Arg) variant has not been reported in individuals with HOXB13-related conditions in the published literature. The frequency of this variant in the general population, 0.00026 (4/15280 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003980054	SCV004795388	uncertain significance	HOXB13-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The HOXB13 c.610G>A variant is predicted to result in the amino acid substitution p.Gly204Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/483477/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.