ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.526C>T (p.Arg176Ter)

gnomAD frequency: 0.00003  dbSNP: rs199475575
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000179282 SCV000852175 pathogenic Phenylketonuria 2018-08-13 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients in this study (PMID:10394930; PMID:26600521); PM3_Strong: Identified in 6 patients, in trans with R243Q and R241C (both pathogenic) (PMID:26600521). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong).
Eurofins Ntd Llc (ga) RCV000088971 SCV000231507 pathogenic not provided 2014-08-08 criteria provided, single submitter clinical testing
Invitae RCV000179282 SCV000629197 pathogenic Phenylketonuria 2024-01-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg176*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs199475575, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with phenyketonuria (PMID: 8268925, 17935162, 23514811, 26413448, 26503515). ClinVar contains an entry for this variant (Variation ID: 102723). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179282 SCV000696453 pathogenic Phenylketonuria 2016-03-03 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000179282 SCV000744099 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000179282 SCV000745573 pathogenic Phenylketonuria 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088971 SCV000888349 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000179282 SCV000893951 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000179282 SCV001810542 pathogenic Phenylketonuria 2021-07-22 criteria provided, single submitter clinical testing
3billion RCV000179282 SCV002573258 pathogenic Phenylketonuria 2022-09-01 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%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. 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: 26600521). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000102723 / PMID: 8268925). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV000179282 SCV004201383 pathogenic Phenylketonuria 2023-10-05 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088971 SCV000119574 not provided not provided no assertion provided not provided
Counsyl RCV000179282 SCV000485295 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000179282 SCV001455097 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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