ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1A>G (p.Met1Val) (rs62514891)

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Total submissions: 8
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088868 SCV000331821 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000000616 SCV001215549 pathogenic Phenylketonuria 2019-12-23 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, ExAC 0.002%). This variant has been observed to be homozygous and in combination with another PAH variant in several individuals affected with PKU (PMID: 2574002, 26666653, 1301193, Invitae). ClinVar contains an entry for this variant (Variation ID: 586). This variant has been reported to affect PAH protein function (PMID:1301201). This variant disrupts the p.Met1 amino acid residue in PAH. Another variant that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 24941924), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000616 SCV000020766 pathogenic Phenylketonuria 1992-07-01 no assertion criteria provided literature only
OMIM RCV000000617 SCV000020767 pathogenic Hyperphenylalaninemia, non-pku 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

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