Submissions for variant NM_032492.4(JAGN1):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00003  dbSNP: rs587777727

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Klein lab, Ludwig-Maximilians-University	RCV000170600	SCV000223152	pathogenic	Severe congenital neutropenia	2013-01-01	criteria provided, single submitter	in vitro	Neutropenia patients with mutations in JAGN1 respond poorly to treatment with recombinant human G-CSF
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144162	SCV001491910	uncertain significance	Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the JAGN1 mRNA. The next in-frame methionine is located at codon 25. This variant is present in population databases (rs587777727, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with primary immunodeficiency and/or severe congenital neutropenia (PMID: 25129144, 32888943, 33718801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156113). This variant disrupts the p.Met1 amino acid residue in JAGN1. Other variant(s) that disrupt this residue have been determined to be benign based on frequency in the population databases (c.1A>G, ExAC). Therefore the functional significance of this variant is uncertain. 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	RCV001785475	SCV002027856	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Another variant affecting the initiation codon, c.1A>G, is observed in 0.35% (940/266206 alleles) in large population cohorts, including 14 homozygous observations (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32419428, 25129144, 32888943, 33718801)
Genomics Facility, Ludwig-Maximilians-Universität München	RCV000144162	SCV002073871	pathogenic	Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency	2021-12-28	criteria provided, single submitter	clinical testing
OMIM	RCV000144162	SCV000189242	pathogenic	Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency	2014-09-01	no assertion criteria provided	literature only