rs104894142
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000369887.4(CYP17A1):c.1084C>T(p.Arg362Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,610,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R362H) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000369887.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP17A1 | NM_000102.4 | c.1084C>T | p.Arg362Cys | missense_variant | 6/8 | ENST00000369887.4 | NP_000093.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP17A1 | ENST00000369887.4 | c.1084C>T | p.Arg362Cys | missense_variant | 6/8 | 1 | NM_000102.4 | ENSP00000358903 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251224Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
GnomAD4 exome AF: 0.00000891 AC: 13AN: 1458564Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6AN XY: 725814
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Deficiency of steroid 17-alpha-monooxygenase Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 27, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 25, 2021 | - - |
CYP17A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 25, 2023 | The CYP17A1 c.1084C>T variant is predicted to result in the amino acid substitution p.Arg362Cys. This variant has been reported to be pathogenic for steroid-17 alpha-hydroxylase deficiency due to completely inactivated enzyme activity (see for example at Fernández-Cancio et al. 2017. PubMed ID: 28376482; Martin et al. 2003. PubMed ID: 14671162; Costa-Santos et al. 2004. PubMed ID: 14715827). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-104592323-G-A). This variant is interpreted as pathogenic. - |
17-alpha-hydroxylase/17,20-lyase deficiency, combined complete Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 17, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 362 of the CYP17A1 protein (p.Arg362Cys). This variant is present in population databases (rs104894142, gnomAD 0.006%). This missense change has been observed in individuals with adrenal hyperplasia (PMID: 14715827, 17379008, 21340157, 29595516). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP17A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 14715827). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Congenital adrenal hyperplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2023 | Variant summary: CYP17A1 c.1084C>T (p.Arg362Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251224 control chromosomes. c.1084C>T has been widely reported in the literature as biallelic genotypes in multiple individuals affected with Congenital Adrenal Hyperplasia (example, Cosa Santos_2004). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal 17-alpha hydroxylase enzyme activity in-vitro (example, Cosa Santos_2004). Two 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at