Submissions for variant NM_003467.3(CXCR4):c.157A>C (p.Ile53Leu)

gnomAD frequency: 0.00045  dbSNP: rs56400844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000880790	SCV001023912	benign	Warts, hypogammaglobulinemia, infections, and myelokathexis	2024-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001817066	SCV002066982	likely benign	not specified	2021-08-09	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002065464	SCV002496093	uncertain significance	WHIM syndrome 1	2021-07-09	criteria provided, single submitter	clinical testing	CXCR4 NM_003467.2 exon 2 p.Ile53Leu (c.157A>C): This variant has been reported in the literature in at least 3 individuals: 2 with juvenile idiopathic arthritis and 1 with primary immunodeficiency (Finkel 2016 PMID:27005825, Platt 2021 PMID:32888943). This variant is present in 0.7% (11/15286) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-136115771-T-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:709395). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001357354	SCV003916133	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	CXCR4: BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357354	SCV001552806	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CXCR4 p.Ile57Leu variant was identified in 2 of 960 proband chromosomes (frequency: 0.0021) from individuals with juvenile idiopathic arthritis and was not identified in 960 control chromosomes from healthy individuals (Finkel_2016_PMID:27005825). The variant was identified in dbSNP (ID: rs56400844) but was not identified in ClinVar or Cosmic. The variant was identified in control databases in 135 of 268326 chromosomes at a frequency of 0.0005031 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Ashkenazi Jewish in 59 of 9862 chromosomes (freq: 0.005983), Latino in 22 of 35108 chromosomes (freq: 0.000627), Other in 3 of 6708 chromosomes (freq: 0.000447), European (non-Finnish) in 49 of 118150 chromosomes (freq: 0.000415) and African in 2 of 23614 chromosomes (freq: 0.000085), but was not observed in the East Asian, European (Finnish), or South Asian populations. The p.Ile57 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.