ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs199475613
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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 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV000560269 SCV000629196 pathogenic Phenylketonuria 2021-02-24 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. 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 has been observed in individual(s) with PAH-related conditions (PMID: 26600521, 28982351, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102716). This variant is not present in population databases (ExAC no frequency). 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.
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
Natera, Inc. RCV000560269 SCV002088660 uncertain significance Phenylketonuria 2021-01-09 no assertion criteria provided clinical testing

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