Submissions for variant NM_000277.3(PAH):c.*144A>G

gnomAD frequency: 0.00007  dbSNP: rs375319584

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000814338	SCV001572839	uncertain significance	Phenylketonuria	2020-12-23	reviewed by expert panel	curation	The NM_000277.3(PAH):c.*144A>G (ClinVar variant ID 657680) is a 3’ UTR variant in PAH. The variant has been previously reported as a single heterozygous variant in a proband with classic PKU (PMID: 20188615), with plasma Phe 1105 umol/L; BH4 deficiency does not appear to have been formally excluded (PP4). The authors speculated that the variant could “either affect the half life of the mRNA or its translation efficiency,” but did not perform functional validation studies. The variant was absent in the mother, who was unaffected, and present as a single heterozygous variant in the father, who was also unaffected. The authors were unable to detect a second variant in the (affected) proband, which they argued could be due to it being “located in PAH intronic regions not covered in the screening strategy.” It has also been found as a single heterozygous variant in a screening study of 3,552 healthy Japanese adults (PMID: 30887117). In ClinVar (ClinVar variant ID 657680), it is classified as VUS by one lab and Likely Benign by one lab, based on the above literature reports and uncertain functional consequences. Four heterozygotes and zero homozygotes are present for the variant in gnomAD; corresponding to a global AF of 0.000127 and maximum population frequency of 0.00128 (East Asian population), less than the 0.002 frequency threshold for use of BS1 and greater than the 0.0002 frequency threshold for use of PM2. The variant is predicted to not significantly alter splicing by multiple predictors (Splice AI score 0.00, MaxEntScan score variation 0.00%) (BP4). Classification: VUS Supporting Criteria: PP4; BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814338	SCV000954742	likely benign	Phenylketonuria	2024-04-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000814338	SCV001268940	likely benign	Phenylketonuria	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003948002	SCV004759045	likely benign	PAH-related disorder	2021-03-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).