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

gnomAD frequency: 0.00001  dbSNP: rs199475613

Total submissions: 5

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	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). 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. 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. 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