Submissions for variant NM_000418.4(IL4R):c.1774G>T (p.Val592Leu)

gnomAD frequency: 0.00156  dbSNP: rs138392496

Total submissions: 3

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	RCV001027790	SCV001190399	uncertain significance	IgE responsiveness, atopic; Susceptibility to HIV infection	2021-03-30	criteria provided, single submitter	clinical testing	IL4R NM_000418.3 exon 11 p.Val592Leu (c.1774G>T): This variant has not been reported in the literature and is present in 0.6% (150/24724) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-27374447-G-T). This variant amino acid Leucine (Leu) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Breakthrough Genomics, Breakthrough Genomics	RCV001358382	SCV005194288	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358382	SCV001554099	uncertain significance	not provided		no assertion criteria provided	clinical testing	The IL4R p.Val592Leu variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138392496) and in control databases in 164 of 281398 chromosomes at a frequency of 0.000583 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 150 of 24724 chromosomes (freq: 0.006067), Latino in 11 of 35378 chromosomes (freq: 0.000311) and European (non-Finnish) in 3 of 128206 chromosomes (freq: 0.000023); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Val592 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.