Submissions for variant NM_000277.3(PAH):c.140C>T (p.Ala47Val)

gnomAD frequency: 0.00001  dbSNP: rs118203925

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001200011	SCV001370868	likely pathogenic	Phenylketonuria	2020-05-22	reviewed by expert panel	curation	The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Invitae	RCV001200011	SCV001590614	pathogenic	Phenylketonuria	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the PAH protein (p.Ala47Val). This variant is present in population databases (rs118203925, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 630). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 11326337, 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001200011	SCV004038881	pathogenic	Phenylketonuria	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: PAH c.140C>T (p.Ala47Val) 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 allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.140C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and -mild hyperphenylalaninemia (examples: Aldamiz-Echevarria_2016, Bayat_2016, Ho_2013). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that this missense change affects PAH function (examples: Gjetting_MGM_2001, Gjetting_AJHG_2001, and Himmelreich_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11161839, 11326337, 30037505, 27121329, 24368688, and 26542770). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000662	SCV000020812	pathogenic	Hyperphenylalaninemia	1994-05-15	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088839	SCV000119431	not provided	not provided		no assertion provided	not provided