ClinVar Miner

Submissions for variant NM_000102.4(CYP17A1):c.1118A>T (p.His373Leu)

gnomAD frequency: 0.00001  dbSNP: rs760695410
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000809884 SCV000950065 pathogenic not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 373 of the CYP17A1 protein (p.His373Leu). This variant is present in population databases (rs760695410, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 8245018, 10877510, 11549876, 12706306, 24140098). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 654004). 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: 8245018). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001830766 SCV004215380 pathogenic Deficiency of steroid 17-alpha-monooxygenase 2024-02-22 criteria provided, single submitter clinical testing
3billion RCV001830766 SCV005904222 pathogenic Deficiency of steroid 17-alpha-monooxygenase 2023-06-21 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: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP17A1 related disorder (ClinVar ID: VCV000654004 /PMID: 8245018). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10877510, 11549876, 12706306, 24140098, 8245018). Different missense changes at the same codon (p.His373Asn, p.His373Asp, p.His373Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001065950, VCV001065951, VCV001460105 /PMID: 19470621, 19793597, 29278670). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc. RCV001830766 SCV002091085 pathogenic Deficiency of steroid 17-alpha-monooxygenase 2020-10-13 no assertion criteria provided clinical testing

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