Submissions for variant NM_006118.4(HAX1):c.724C>T (p.Arg242Ter)

gnomAD frequency: 0.00004  dbSNP: rs760377093

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778184	SCV000914348	uncertain significance	Kostmann syndrome	2017-09-14	criteria provided, single submitter	clinical testing	The HAX1 c.724C>T (p.Arg242Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe congenital neutropenia.
Genetic Services Laboratory, University of Chicago	RCV001816833	SCV002069241	uncertain significance	not specified	2018-09-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778184	SCV003445513	uncertain significance	Kostmann syndrome	2024-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg242*) in the HAX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the HAX1 protein. This variant is present in population databases (rs760377093, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with HAX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 631565). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.