ClinVar Miner

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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