Submissions for variant NM_003467.3(CXCR4):c.1013C>G (p.Ser338Ter)

dbSNP: rs104893626

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000015067	SCV000898643	pathogenic	Warts, hypogammaglobulinemia, infections, and myelokathexis	2017-11-02	criteria provided, single submitter	clinical testing	CXCR4 NM_003467.2 exon 2 p.Ser338* (c.1013C>G): This variant has been reported in the literature in at least 2 individuals with WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis), segregating with disease in 1 affected family member (Balabanian 2005 PMID:15536153, Alapi 2007 PMID:17087743, Lagane 2008 PMID:18436740). One of these individuals was found to have this variant de novo. This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740). In summary, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001568992	SCV001472850	pathogenic	not provided	2019-12-23	criteria provided, single submitter	clinical testing	The CXCR4 c.1013C>G; p.Ser338Ter variant (rs104893626) is reported in the literature in several individuals affected with WHIM syndrome (Alapi 2007, Balabanian 2005, Tassone 2009). In one instance, the variant was observed in an affected proband but was absent from both parents, suggesting a de novo origin (Alapi 2007). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the CXCR4 gene. While this may not lead to nonsense-mediated decay, it is expected to truncate 15 amino acids from the C-terminal domain, including several residues functionally critical for receptor internalization (Orsini 1999). Indeed, functional characterization of patient cells or cultured cells expressing the p.Ser338Ter variant suggests the variant protein exhibits defective internalization, aberrant interactions with binding partners, and increased signaling activity (Balabanian 2005, Lagane 2008, Tassone 2009). Based on available information, the p.Ser338Ter variant is considered to be pathogenic. References: Alapi K et al. Recurrent CXCR4 sequence variation in a girl with WHIM syndrome. Eur J Haematol. 2007 Jan;78(1):86-8. Balabanian K et al. WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood. 2005 Mar 15;105(6):2449-57. Lagane B et al. CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood. 2008 Jul 1;112(1):34-44. Orsini MJ et al. Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identification of residues in the c-terminal tail that mediate receptor internalization. J Biol Chem. 1999 Oct 22;274(43):31076-86. Tassone L et al. Clinical and genetic diagnosis of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome in 10 patients. J Allergy Clin Immunol. 2009 May;123(5):1170-3, 1173.e1-3.
GeneDx	RCV001568992	SCV001792959	pathogenic	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with delayed or failed receptor internalization (Balabanian et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 15 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26659815, 19321197, 15536153, 23009155, 19878273, 25819228, 25371371, 18436740, 26997321, 17087743)
Fulgent Genetics, Fulgent Genetics	RCV001801240	SCV002777957	pathogenic	WHIM syndrome 1	2021-10-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001801240	SCV003919869	pathogenic	WHIM syndrome 1	2021-03-30	criteria provided, single submitter	clinical testing	CXCR4 NM_003467 exon 2 p.Ser338* (c.1013C>G): This variant has been reported in the literature in at least 2 individuals with WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis), segregating with disease in 1 affected family member (Balabanian 2005 PMID:15536153, Alapi 2007 PMID:17087743, Lagane 2008 PMID:18436740). One of these individuals was found to have this variant de novo. This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740). In summary, this variant is classified as pathogenic.
OMIM	RCV001801240	SCV000035323	pathogenic	WHIM syndrome 1	2008-07-01	no assertion criteria provided	literature only