ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.442G>A (p.Gly148Ser)

gnomAD frequency: 0.00001  dbSNP: rs80297647
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001053534 SCV001250531 likely pathogenic Phenylketonuria 2019-12-22 reviewed by expert panel curation The PAH variant c.442G>A (p.Gly148Ser) has been reported in three individuals with PHA deficiency (Phe levels >120 microM). One patient from the Northeastern region of the US, (PMID: 8659548)(PMID:10429004), one patient from Europe (PMID: 10679941), and one patient from the Campania Region in Southern Italy with mild PKU (Phe between 600 and 1200 microM) (PMID: 17096675). The variant c.442G>A (p.Gly148Ser) was document with the pathogenic variant c.194T>C (p.Ile65Thr)(ClinVar ID: 636), and with the pathogenic variant c.473G>A (p.Arg158Gln)(ClinVar ID: 587) (PMID: 8535445). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the African population (0.00006). In silico modeling predicts that this missense variant is damaging by SIFT, probably damaging by Polyphen 2 and disease causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4 .
Invitae RCV001053534 SCV001217801 pathogenic Phenylketonuria 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 148 of the PAH protein (p.Gly148Ser). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 102680). This missense change has been observed in individual(s) with phenylketonuria (PMID: 7726156, 8535445, 9012412, 10679941; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs80297647, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000088928 SCV001786390 likely pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in individuals with PAH deficiency, however additional clinical information and information about a second PAH variant were not provided (Hennermann et al., 2000; Tyfield et al., 1997; Guldberg et al., 1996); This variant is associated with the following publications: (PMID: 32668217, 10394930, 8659548, 9012412, 10679941, 17924342, 10203137, 12649065, 21504866, 7726156)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001053534 SCV002572161 likely pathogenic Phenylketonuria 2022-08-19 criteria provided, single submitter clinical testing Variant summary: PAH c.442G>A (p.Gly148Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251264 control chromosomes (gnomAD). c.442G>A has been reported in the literature in bi-allelic individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Ramus_1995 and Hillert_2020). These data indicate that the variant is likely to be associated with disease. In addition, other missense variants in the same residue (G148R, G148D, G148V) have been reported in the Human Gene Mutation Database in association with Phenylalanine Hydroxylase Deficiency and G148D/V have been classified as likely pathogenic in ClinVar, supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Three submitters including an expert panel classified the variant as likely pathogenic and one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV001053534 SCV004201976 pathogenic Phenylketonuria 2022-07-12 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088928 SCV000119527 not provided not provided no assertion provided not provided
Natera, Inc. RCV001053534 SCV001455105 uncertain significance Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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