Submissions for variant NM_173483.4(CYP4F22):c.1303C>T (p.His435Tyr)

gnomAD frequency: 0.00008  dbSNP: rs118203935

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412942	SCV000490953	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that protein activity decreased significantly compared to wild-type protein activity (Ohno et al., 2015); This variant is associated with the following publications: (PMID: 32069299, 27535533, 31130284, 26646773, 16436457, 26056268)
Baylor Genetics	RCV000000957	SCV001523986	pathogenic	Autosomal recessive congenital ichthyosis 5	2019-10-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412942	SCV001584126	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 435 of the CYP4F22 protein (p.His435Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs118203935, ExAC 0.01%). This missense change has been observed in individuals with non-syndromic autosomal recessive congenital ichthyosis (PMID: 16436457, 26646773). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582456	SCV001821385	pathogenic	Lamellar ichthyosis	2021-08-24	criteria provided, single submitter	clinical testing	Variant summary: CYP4F22 c.1303C>T (p.His435Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP4F22 causing Lamellar Ichthyosis (5.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.1303C>T has been reported in the literature in numerous individuals affected with Lamellar Ichthyosis, including segregating in multiple families (eg. Lefevre_2006, Esperon-Moldes_2020, etc). Functional studies have shown the variant result in significantly decreased omega-hydroxylase activity compared to wild-type (Ohno_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000000957	SCV002018133	pathogenic	Autosomal recessive congenital ichthyosis 5	2020-09-24	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000000957	SCV003841769	pathogenic	Autosomal recessive congenital ichthyosis 5	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000909). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16436457). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 16436457). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000000957	SCV005374225	pathogenic	Autosomal recessive congenital ichthyosis 5	2024-09-22	criteria provided, single submitter	clinical testing
OMIM	RCV000000957	SCV000021107	pathogenic	Autosomal recessive congenital ichthyosis 5	2006-03-01	no assertion criteria provided	literature only
Institute for Human Genetics, University Medical Center Freiburg	RCV000000957	SCV000804497	pathogenic	Autosomal recessive congenital ichthyosis 5	2018-04-23	no assertion criteria provided	clinical testing