Submissions for variant NM_000277.3(PAH):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs62514891

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000616	SCV000852133	pathogenic	Phenylketonuria	2018-08-07	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Initiation codon variant; PM2: gnomAD MAF=0.00002; PP4_Moderate: Seen in PKU patients. BH4 disorders ruled out. (PMID:2574002); PS3: <3% (PMID:9450897). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PS3).
Counsyl	RCV000000616	SCV000220962	likely pathogenic	Phenylketonuria	2014-12-17	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000088868	SCV000331821	pathogenic	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000616	SCV000696442	pathogenic	Phenylketonuria	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide at the translation start site and 3/4 in silico tools predict damaging outcome (SNPs&GO not captured here due to low reliability index value). A functional study showed that the variant leads to non-detectable PAH protein expression and enzymatic activity (John_1992). This variant was found in 1/121238 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited this variant in patients with PKU in homozygous as well as compound heterozygous state (John_1989, John_1992, Lyonnet_1992, Carter_1998, Jeannesson-Thivisol_2915). The patients were of French Canadian/French descent and founder effect due to this variant was indicated in this population. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000616	SCV001215549	pathogenic	Phenylketonuria	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. This variant is present in population databases (rs62514891, gnomAD 0.002%). Disruption of the initiator codon has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 1301193, 2574002, 24941924, 26666653; Invitae). ClinVar contains an entry for this variant (Variation ID: 586). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PAH function (PMID: 1301201). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000088868	SCV001820869	pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Seen in a patient with classic PKU in the presence of a second pathogenic variant in PAH and BH4 responsiveness was unknown (Jeannesson-Thivisol et al., 2015); In vitro functional studies demonstrate a damaging effect of c.1A>G on enzyme activity (John et al., 1992); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32668217, 26666653, 1301201, 2574002, 1609797, 17924342, 9634518, 9450897, 9781015)
OMIM	RCV000000616	SCV000020766	pathogenic	Phenylketonuria	1992-07-01	no assertion criteria provided	literature only
OMIM	RCV000000617	SCV000020767	pathogenic	Hyperphenylalaninemia	1992-07-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088868	SCV000119464	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000616	SCV001459233	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing