ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.511G>A (p.Gly171Arg) (rs199475613)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000560269 SCV000852106 likely pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.966; PP4_Moderate: Detected in PKU patients. BH4 deficiency assessed. Upgraded per ClinGen PAH EP. (PMID:26600521; PMID:23430918); PM3_Strong: Detected with c.611A>G (P/LP) and R408W (P). Upgraded per ClinGen SVI workgroup. (PMID:23430918; PMID:26600521). 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, PP4_Moderate, PM3_Strong).
Counsyl RCV000560269 SCV000799610 uncertain significance Phenylketonuria 2018-05-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088964 SCV000119567 not provided not provided no assertion provided not provided
Invitae RCV000560269 SCV000629196 uncertain significance Phenylketonuria 2017-01-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 171 of the PAH protein (p.Gly171Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PAH-related disease. However, this variant has been reported in a fetus in prenatal diagnosis (PMID: 26600521). In addition, a different variant at this codon, p.Gly171Ala has been reported in an individual affected with mild PKU (PMID: 17924342).  ClinVar contains an entry for this variant (Variation ID: 02716). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function or splicing. Therefore, it has been classified as a Variant of Uncertain Significance.

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