Submissions for variant NM_006118.4(HAX1):c.91del (p.Glu31fs)

gnomAD frequency: 0.00026  dbSNP: rs764082747

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485748	SCV000568065	pathogenic	not provided	2024-05-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19036076, 34426522, 31589614, 32054657, 19499579)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706106	SCV000835138	pathogenic	Kostmann syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (rs764082747, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076, 19499579). ClinVar contains an entry for this variant (Variation ID: 419887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000485748	SCV001450266	likely pathogenic	not provided	2014-12-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000706106	SCV002024945	pathogenic	Kostmann syndrome	2023-10-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000485748	SCV002098330	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000485748	SCV002502270	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000706106	SCV002782074	pathogenic	Kostmann syndrome	2024-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155204	SCV003845036	pathogenic	Severe congenital neutropenia	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00019 in 251294 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in HAX1 causing Severe Congenital Neutropenia (0.00019 vs 0.00079), allowing no conclusion about variant significance. c.91delG has been reported in the literature in individuals affected with Severe Congenital Neutropenia (e.g. Smith_2009, Carlsson_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000706106	SCV005085941	pathogenic	Kostmann syndrome	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with severe congenital neutropenia 3 (MIM#610738). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 58 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with neutropenia and classified as pathogenic in ClinVar (PMID: 37193639). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000485748	SCV005198426	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000485748	SCV005413729	pathogenic	not provided	2024-05-30	criteria provided, single submitter	clinical testing	PM3_strong, PVS1
OMIM	RCV000706106	SCV000025096	pathogenic	Kostmann syndrome	2009-03-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000706106	SCV001461732	pathogenic	Kostmann syndrome	2020-09-16	no assertion criteria provided	clinical testing