Submissions for variant NM_000277.3(PAH):c.223G>C (p.Asp75His)

dbSNP: rs767453024

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001269068	SCV001448291	likely pathogenic	Phenylketonuria	2020-10-16	reviewed by expert panel	curation	This c.223G>C (p.Asp75His) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 29499199, 28982351) detected with the pathogenic variant p.Val399= (PMID: 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 29499199). This variant is absent in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269068	SCV004296188	pathogenic	Phenylketonuria	2022-11-02	criteria provided, single submitter	clinical testing	This variant disrupts the p.Asp75 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 29499199). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 75 of the PAH protein (p.Asp75His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 28982351, 29499199). ClinVar contains an entry for this variant (Variation ID: 987769). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526825	SCV005039915	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: PAH c.223G>C (p.Asp75His) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251374 control chromosomes (gnomAD). c.223G>C has been reported in the literature in individuals affected with Hyperphenylalaninemia or Phenylketonuria (Liu_2017, Wang_2018, Wang_2021, Wang_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28982351, 29499199, 35085585, 33980295). ClinVar contains an entry for this variant (Variation ID: 987769). A ClinGen expert panel has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004545164	SCV005040776	likely pathogenic	Propionic acidemia	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.223G>C (p.Ala75Pro) results in a non-conservative amino acid change located in the N-terminal domain (IPR005481) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250608 control chromosomes (gnomAD). The variant, c.223G>C (aka c.148G>C / A50P) has been reported in the literature in at least two compound heterozygous individuals who were affected with a milder form of Propionic Acidemia (Campeau_1999, Cappuccio_2016). These data indicate that the variant may be associated with disease. A publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased enzyme activity (likely as a result of increased degradation), with a relatively high residual activity (15-30%) in a PCCA-deficient fibroblast system (Clavero_2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.