Submissions for variant NM_000277.3(PAH):c.718T>G (p.Phe240Val)

dbSNP: rs62507337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000667600	SCV002540119	uncertain significance	Phenylketonuria	2020-11-09	reviewed by expert panel	curation	The c.718T>G (p.Phe240Val) variant in PAH has not been reported in the literature detected in an affected patient to our knowledge. This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.978. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3.
Counsyl	RCV000667600	SCV000792078	uncertain significance	Phenylketonuria	2017-06-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667600	SCV002301684	pathogenic	Phenylketonuria	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the PAH protein (p.Phe240Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe240 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102801).
GeneDx	RCV000089052	SCV002762276	uncertain significance	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002514546	SCV003536109	uncertain significance	Inborn genetic diseases	2022-11-15	criteria provided, single submitter	clinical testing	The c.718T>G (p.F240V) alteration is located in exon 7 (coding exon 7) of the PAH gene. This alteration results from a T to G substitution at nucleotide position 718, causing the phenylalanine (F) at amino acid position 240 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525872	SCV005039508	uncertain significance	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: PAH c.718T>G (p.Phe240Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 250956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.718T>G in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 102801). Based on the evidence outlined above, the variant was classified as uncertain significance.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089052	SCV000119657	not provided	not provided		no assertion provided	not provided