rs104894149

chr10-102832611-G-Achr10-102832611-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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 Likely 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.01

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 4) in uniprot entity CP17A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000102.4
• 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 ClinVar as [Pathogenic]. Clinvar id is 1787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 [Likely_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	UniProt
CYP17A1	NM_000102.4	c.1039C>T	p.Arg347Cys	missense_variant	6/8	ENST00000369887.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP17A1	ENST00000369887.4	c.1039C>T	p.Arg347Cys	missense_variant	6/8	1	NM_000102.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251414 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135886

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: 8 AN: 1452086 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 723254

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2023	- -
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). -

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

Invitae

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 15, 2021

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 at-least three individuals with isolated 17,20-lyase deficiency presenting as Androgen insensitivity syndrome (AIS) (example, can den Akker_2002, ten Kate-Booij_2004) and has subsequently been cited by others in the field. These data indicate that the variant may be associated with disease. 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.48	T
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	D
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

Other links and lift over

dbSNP: rs104894149; hg19: chr10-104592368;