Submissions for variant NM_000277.3(PAH):c.284_285delinsCA (p.Ile95Thr)

dbSNP: rs281865432

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106353	SCV001250558	uncertain significance	Phenylketonuria	2020-01-25	reviewed by expert panel	curation	The c.284_285delTCinsCA (p.Ile95Thr) indel variant in PAH has not been reported in the literature to our knowledge. It has been included in BioPKU/PAHdb (PAH0793) by online submission (Namour et al.,2013). It is absent from ExAC, gnomAD, 1000G, and ESP. There is not consensus among predictions of pathogenicity. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000106353	SCV001374395	uncertain significance	Phenylketonuria	2019-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 95 of the PAH protein (p.Ile95Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 120272). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant disrupts the p.Ile95 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722928, 1709636, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
PreventionGenetics, part of Exact Sciences	RCV003390792	SCV004112681	uncertain significance	PAH-related disorder	2023-07-13	criteria provided, single submitter	clinical testing	The PAH c.284_285delinsCA variant is predicted to result in an in-frame deletion and insertion. which is predicted to result in the amino acid substitution p.Ile95Thr. This variant has been interpreted by the ClinGen PAH Variant Curation Expert Panel as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/120272/). A different amino acid substitution at this position (p.Ile95Phe) has been reported in several patients with phenylketonuria (Bercovich D et al 2008. PubMed ID: 18299955; Rajabi F et al 2019. PubMed ID: 31623983). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106353	SCV000143852	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.