ClinVar Miner

Submissions for variant NM_000102.4(CYP17A1):c.1435_1438dup (p.Pro480fs) (rs556794126)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498913 SCV000589608 pathogenic not provided 2017-06-23 criteria provided, single submitter clinical testing The c.1435_1438dupATCC variant has been reported previously in the homozygous state in association with 17 alpha-hydroxylase/17,20-lyase deficiency (Kagimoto et al., 1988; Kagimoto et al., 1989; Imai et al., 1992). The duplication causes a frameshift starting with codon Proline 480, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Pro480HisfsX27. This variant is predicted to cause loss of normal protein function through protein truncation. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000337017 SCV000360138 uncertain significance Deficiency of steroid 17-alpha-monooxygenase 2017-04-27 criteria provided, single submitter clinical testing The CYP17A1 c.1435_1438dupATCC (p.Pro480HisfsTer27) variant results in a frameshift and is predicted to cause premature termination of the protein. The p.Pro480HisfsTer27 variant has been reported in one study in which it is found in one individual with congenital adrenal hyperplasia in a homozygous state (Kagimoto et al. 1988). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele in a region of poor sequence coverage. In vitro enzyme assays with the p.Pro480HisfsTer27 variant protein showed almost total lack of testicular microsomal 17a-hydroxylase and 17,20-lyase activities (Kagimoto et al. 1988). Based on the potential impact of frameshift variants and evidence from the literature, the p.Pro480HisfsTer27 variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital adrenal hyperplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000498913 SCV000956427 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CYP17A1 gene (p.Pro480Hisfs*27). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the CYP17A1 protein. This variant is present in population databases (rs556794126, ExAC 0.003%). This variant has been observed in individuals affected with congenital adrenal hyperplasia (PMID: 1577471, 2786493). ClinVar contains an entry for this variant (Variation ID: 1777). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000337017 SCV000966996 likely pathogenic Deficiency of steroid 17-alpha-monooxygenase 2018-10-09 criteria provided, single submitter clinical testing The p.Pro480HisfsX27 variant in CYP17A1 has been reported in 7 individuals with 17 alpha-hydroxylase/17,20-lyase deficiency and segregated with disease in 2 aff ected family members from 2 families (Kagimoto 1988, Kagimoto 1989, Imai 1992). It has also been identified in 5/104972 of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 480 and lead s to a premature termination codon 27 amino acids downstream. This termination c odon occurs within the terminal 50 bases of the second to the last exon and is t herefore likely to escape nonsense mediated decay (NMD) and result in a truncate d protein. In summary, although additional studies are required to fully establi sh its clinical significance, the p.Pro480HisfsX27 variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM3, PVS1_Moderate, PP1_Moderate.
OMIM RCV000001849 SCV000022005 pathogenic Complete combined 17-alpha-hydroxylase/17,20-lyase deficiency 1992-04-01 no assertion criteria provided literature only

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