ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.818C>T (p.Ser273Phe) (rs62514953)

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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 RCV000000629 SCV000852145 likely pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC and gnomAD (1 allele); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978; PP4_Moderate: S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup. (PMID:1671881; PMID:8533759; PMID:9012412; PMID:24368688); PM3_Strong: Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines (PMID:24368688). 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).
Baylor Genetics RCV000000629 SCV001163719 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Invitae RCV000000629 SCV001230923 pathogenic Phenylketonuria 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 273 of the PAH protein (p.Ser273Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs62514953, ExAC 0.001%). This variant has been observed in individual(s) with phenylketonuria (PMID: 24368688, 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: 598). 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 disrupts the p.Ser273 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 11142755), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000629 SCV000020779 pathogenic Phenylketonuria 1991-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089111 SCV000119718 not provided not provided no assertion provided not provided

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