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.
ClinVar Genomic variation as it relates to human health
NM_173483.4(CYP4F22):c.1303C>T (p.His435Tyr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_173483.4(CYP4F22):c.1303C>T (p.His435Tyr)
Variation ID: 909 Accession: VCV000000909.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.12 19: 15549170 (GRCh38) [ NCBI UCSC ] 19: 15659981 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 13, 2024 Sep 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_173483.4:c.1303C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_775754.2:p.His435Tyr missense NC_000019.10:g.15549170C>T NC_000019.9:g.15659981C>T NG_007987.1:g.45646C>T Q6NT55:p.His435Tyr - Protein change
- H435Y
- Other names
- -
- Canonical SPDI
- NC_000019.10:15549169:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CYP4F22 | - | - |
GRCh38 GRCh37 |
234 | 252 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000000957.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2021 | RCV000412942.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 24, 2021 | RCV001582456.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Lamellar ichthyosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821385.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001584126.3
First in ClinVar: May 10, 2021 Last updated: Feb 07, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive congenital ichthyosis 5
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018133.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive congenital ichthyosis 5
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374225.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
|
|
Pathogenic
(Oct 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive congenital ichthyosis 5
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001523986.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Jun 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490953.3
First in ClinVar: Jan 09, 2017 Last updated: Jul 18, 2021 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive congenital ichthyosis 5
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841769.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
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. … (more)
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. (less)
Clinical Features:
Ichthyosis (present) , Global developmental delay (present) , Abnormal facial shape (present)
|
|
|
Pathogenic
(Mar 01, 2006)
|
no assertion criteria provided
Method: literature only
|
ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021107.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 1 French and 5 Algerian consanguineous families with autosomal recessive congenital ichthyosis (ARCI5; 604777) of the lamellar type, Lefevre et al. (2006) identified homozygosity … (more)
In 1 French and 5 Algerian consanguineous families with autosomal recessive congenital ichthyosis (ARCI5; 604777) of the lamellar type, Lefevre et al. (2006) identified homozygosity for a 1303C-T transition in exon 10 of the CYP4F22 gene, resulting in a his435-to-tyr (H435Y) substitution in a highly conserved region of the protein. (less)
|
|
|
Pathogenic
(Apr 23, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive congenital ichthyosis 5
Affected status: yes
Allele origin:
germline
|
Institute for Human Genetics, University Medical Center Freiburg
Accession: SCV000804497.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
Comment:
Comment:
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.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
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)
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
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)
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation. | Esperón-Moldes U | PloS one | 2020 | PMID: 32069299 |
| Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby. | Noguera-Morel L | Pediatric dermatology | 2016 | PMID: 26646773 |
| Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. | Ohno Y | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 26056268 |
| Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. | Lefèvre C | Human molecular genetics | 2006 | PMID: 16436457 |
Text-mined citations for rs118203935 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.