rs104894149

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000102.4(CYP17A1):c.1039C>T(p.Arg347Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,452,086 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. R347H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CYP17A1
NM_000102.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.01

Variant links:

Genes affected

CYP17A1 (HGNC:2593): (cytochrome P450 family 17 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Mutations in this gene are associated with isolated steroid-17 alpha-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia. [provided by RefSeq, Jul 2008]

CYP17A1 links:

WBP1L (HGNC:23510): (WW domain binding protein 1 like) Predicted to enable ubiquitin protein ligase binding activity. Predicted to act upstream of or within CXCL12-activated CXCR4 signaling pathway; hemopoiesis; and positive regulation of protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

WBP1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-102832610-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 10-102832611-G-A is Pathogenic according to our data. Variant chr10-102832611-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102832611-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP17A1	NM_000102.4 linkuse as main transcript	c.1039C>T	p.Arg347Cys	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 linkuse as main transcript	c.1039C>T	p.Arg347Cys	missense_variant	6/8	1	NM_000102.4	ENSP00000358903	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1452086

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Apr 23, 2021	The CYP17A1 p.Arg347Cys variant is in exon 6 of 8 and falls within the redox partner interaction domain of the protein. It is rare in large population cohorts (1 of 251,414 alleles, gnomAD v2.1.1). In vitro assays show that the p.Arg347Cys alteration leads to partial loss of 17-alpha-hydroxylase activity with near complete loss of 17,20-lyase activity. Two individuals with 46,XY karyotypes and partial 17α-hydroxylase deficiency and complete 17,20-lyase deficiency were found to carry the p.Arg347Cys along with a second pathogenic variant (See patients 3 and 4 from PMID: 12466376). A different missense variant at this position (p.Arg347His) has been observed in the homozygous state in multiple affected individuals (PMID: 12466376, PMID: 9326943). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

17-alpha-hydroxylase/17,20-lyase deficiency, combined partial

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 347 of the CYP17A1 protein (p.Arg347Cys). This variant is present in population databases (rs104894149, gnomAD 0.004%). This missense change has been observed in individual(s) with isolated 17,20-lyase deficiency (PMID: 12466376). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1794). 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: 12466376). This variant disrupts the p.Arg347 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326943, 9601054, 12466376, 27426448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Jun 05, 2024

Variant summary: CYP17A1 c.1039C>T (p.Arg347Cys) results in a non-conservative amino acid change located in the redox partner interaction domain (van den Akker_2002) of 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 251414 control chromosomes. c.1039C>T has been reported in the literature as a compound heterozygous genotype in individuals with isolated 17,20-lyase deficiency presenting as Androgen insensitivity syndrome (AIS) (e.g., van den Akker_2002, ten Kate-Booij_2004) and in at least one homozygous individual affected with 17-Hydroxylase/17,20-lyase deficiency (e.g. Yamagata_2022). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1040G>A, p.Arg347His), supporting the critical relevance of codon 347 to CYP17A1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal 17,20-Lyase activity and 13.6% of normal 17-alpha hydroxylase activity when expressed in COS-1 cells (van den Akker_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12466376, 14747197, 34483146). ClinVar contains an entry for this variant (Variation ID: 1794). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;.;D;.;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.8

.;.;H;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-7.7

.;.;D;.;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

.;.;D;.;.

Sift4G

Uncertain

0.0050

.;.;D;.;.

Polyphen

1.0

.;.;D;.;.

Vest4

0.94

MutPred

0.93

.;.;Loss of disorder (P = 0.0337);.;Loss of disorder (P = 0.0337);

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

1.9

Varity_R

0.88

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over