Submissions for variant NM_173483.4(CYP4F22):c.712G>A (p.Ala238Thr)

gnomAD frequency: 0.00003  dbSNP: rs572278771

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000912869	SCV001057994	likely benign	not provided	2024-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298734	SCV002599029	likely benign	not specified	2022-09-03	criteria provided, single submitter	clinical testing	Variant summary: CYP4F22 c.712G>A (p.Ala238Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251372 control chromosomes (gnomAD), predominantly at a frequency of 0.0062 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP4F22 causing Lamellar Ichthyosis (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.712G>A has been reported in the literature in individuals affected with Congenital Ichthyosis (Scott_2013, Hotz_2018), however these reports do not provide unequivocal conclusions about association of the variant with disease. When assayed for -hydroxylase activity in a cell-based assay, the variant was found to have comparable activity as WT (Nohara_2021). Three ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: one classified the variant as pathogenic, one as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Human Genetics, University Medical Center Freiburg	RCV000678431	SCV000804505	pathogenic	Autosomal recessive congenital ichthyosis 5	2018-04-23	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000678431	SCV000854736	uncertain significance	Autosomal recessive congenital ichthyosis 5	2018-07-31	no assertion criteria provided	clinical testing