Submissions for variant NM_000277.3(PAH):c.1199G>C (p.Arg400Thr)

dbSNP: rs199475658

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001543634	SCV001762299	pathogenic	Phenylketonuria	2020-06-05	reviewed by expert panel	curation	The c.1199G>C (p.Arg400Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 16256386, 19915519, 23932990). This variant is absent in population databases. It has been detected with pathogenic variants: IVS7+2T>A, p.R243Q, p.G346R (PMID: 16256386); and in trans with IVS4+3G＞C, p.His107Arg, EX6-96A＞G, p.Arg243Gln, IVS4-1G＞A (PMID: 29316886). Computational prediction tools and conservation analysis are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate.
Eurofins Ntd Llc (ga)	RCV000088796	SCV000709068	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001543634	SCV004294256	pathogenic	Phenylketonuria	2023-09-15	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1199G nucleotide in the PAH gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 16256386). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 102562). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26600521, 29176022). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 400 of the PAH protein (p.Arg400Thr). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001543634	SCV006071990	pathogenic	Phenylketonuria	2025-03-31	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1199G>C (p.Arg400Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a cryptic 5' donor site. One predicts the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251264 control chromosomes. c.1199G>C has been reported in the presumed compound heterozygous state in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Li_2018, Liu_2017, Song_2005, Wang_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30050108, 28982351, 16256386, 29176022). ClinVar contains an entry for this variant (Variation ID: 102562). Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088796	SCV000119383	not provided	not provided		no assertion provided	not provided