Submissions for variant NM_000277.3(PAH):c.581T>C (p.Leu194Pro) (rs5030844)

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Total submissions: 5

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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	2018-08-10	criteria provided, single submitter	clinical testing	The L194P variant has also been previously reported inindividuals with PKU (Zschocke et al., 1995; Tyfield et al., 1997; Utz et al., 2012; Ho et al., 2014;Manti et al., 2016). It is unknown if this variant is responsive to BH4 therapy (Jeannesson-Thivisol etal., 2015).
Invitae	RCV000411842	SCV001407997	pathogenic	Phenylketonuria	2019-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with proline at codon 194 of the PAH protein (p.Leu194Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs5030844, ExAC 0.001%). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria or hyperphenilalanemia (PMID: 7981714, 16601866, 22112818, 26666653, 24368688, 24350308, 23430918). ClinVar contains an entry for this variant (Variation ID: 102742). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088991	SCV000119595	not provided	not provided		no assertion provided	not provided

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