Submissions for variant NM_000277.3(PAH):c.350C>T (p.Thr117Ile)

gnomAD frequency: 0.00005  dbSNP: rs281865439

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106354	SCV000852134	uncertain significance	Phenylketonuria	2018-09-28	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC& gnomAD (MAF 0.00018). Absent from 1000G, ESP. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2).
Illumina Laboratory Services, Illumina	RCV000106354	SCV001272692	uncertain significance	Phenylketonuria	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
3billion	RCV000106354	SCV002521621	uncertain significance	Phenylketonuria	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.48; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PAH related disorder (PMID: 32668217). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Invitae	RCV000106354	SCV003451089	uncertain significance	Phenylketonuria	2022-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 117 of the PAH protein (p.Thr117Ile). This variant is present in population databases (rs281865439, gnomAD 0.009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 120273). 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: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106354	SCV000143853	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.