Submissions for variant NM_000277.3(PAH):c.935G>T (p.Gly312Val)

dbSNP: rs62642915

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001972839	SCV004222644	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The NM_000277.3:c.935G>T (p.Gly312Val) is a missense variant in exon 9/13 of PAH. The variant was found to reduce PAH enzymatic activity to 6-7% of wild-type enzyme activity in transfected cells (PMID: 18590700) (PS3_supporting). The variant has been noted in at least six PKU patients with BH4 deficiency excluded (PP4_Moderate), five of whom harbored it in confirmed trans with a Pathogenic or Likely Pathogenic variant (5 points; PM3_VeryStrong). The variant has been reported as a single heterozygous variant in a Chinese patient with mild PKU; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes and by sequencing of genes in the BH4 cofactor metabolism pathway (PMID: 14722928). It has also been found in confirmed trans with c.913-7A>G (Likely Pathogenic per ClinGen PAH VCEP) in a Chinese patient with classic PKU (plasma Phe ≥ 1200 μmol/L); BH4 deficiency was said to be ruled out (PMID: 24401910). It was found in four Chinese PKU patients (BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes and by sequencing of genes in the BH4 cofactor metabolism pathway) in the following cases: two patients with mild hyperphenylalanemia in confirmed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP); one patient with classic PKU in confirmed trans with the p.R413P variant (Pathogenic per ClinGen PAH VCEP); and one patient with mild hyperphenylalanemia in confirmed trans with the p.T372S variant (Likely Pathogenic per ClinGen PAH VCEP) (PMID: 30050108). One heterozygote for the variant is present in gnomAD, corresponding to a global frequency of 0.00000398 and a maximum population frequency of 0.0000544 (East Asian), under the frequency cutoff of 0.0002 for use of PM2 (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.942) (PP3). Classification: Pathogenic Supporting Criteria: PM3_VeryStrong; PS3_supporting; PM2_supporting; PP4_Moderate; PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001972839	SCV002246007	pathogenic	Phenylketonuria	2023-01-22	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 24401910, 28982351). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 312 of the PAH protein (p.Gly312Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). ClinVar contains an entry for this variant (Variation ID: 1458264). 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. For these reasons, this variant has been classified as Pathogenic.
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV001972839	SCV004800857	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	PS3+PM2+PM3_S+PP3+PP4_M