Submissions for variant NM_000277.3(PAH):c.581T>C (p.Leu194Pro)

gnomAD frequency: 0.00002  dbSNP: rs5030844

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411842	SCV000852161	likely pathogenic	Phenylketonuria	2018-08-13	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. gnomAD MAF:0.00004.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899; PM3_Strong: Detected in trans with V245A and R261X, both pathogenic (PMID:7981714; PMID:16601866); PP4_Moderate: Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients. (PMID:8533759; PMID:7981714; PMID:9012412; PMID:16601866). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3_Strong, PP4_Moderate).
Counsyl	RCV000411842	SCV000486100	likely pathogenic	Phenylketonuria	2016-03-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000088991	SCV000582140	pathogenic	not provided	2024-10-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11588399, 26655635, 9399896, 10394930, 9012412, 8533759, 24368688, 7477014, 9634518, 22112818, 12173030, 24350308, 23430918, 17924342, 16601866, 7981714, 26666653, 32778825, 32668217)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411842	SCV001407997	pathogenic	Phenylketonuria	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 194 of the PAH protein (p.Leu194Pro). This variant is present in population databases (rs5030844, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenilalanemia (PMID: 7981714, 16601866, 22112818, 23430918, 24350308, 24368688, 26666653). ClinVar contains an entry for this variant (Variation ID: 102742). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Leu194 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 20920871), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000411842	SCV004209717	pathogenic	Phenylketonuria	2022-11-29	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088991	SCV000119595	not provided	not provided		no assertion provided	not provided