Submissions for variant NM_000277.3(PAH):c.1197A>T (p.Val399=)

dbSNP: rs199475584

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000632	SCV000852144	pathogenic	Phenylketonuria	2018-07-28	reviewed by expert panel	curation	The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID: 23271928; PMID: 11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID: 11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID: 11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000632	SCV000696430	pathogenic	Phenylketonuria	2016-08-05	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1197A>T (p.Val399Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. It is located three nucleotides upstream from exon-intron boundary and is predicted to be damaging by MutationTaster. In addition, 2/5 tools predict the variant to attenuate the splice donor site while 4/5 tools predict the variant to attenuate the cryptic splice site located at upstream to this variant position. Functional study by patients RNA analysis as well as minigene assay proves that this variant is a splicing mutation causing skipping of exon 11 (Chao_2001). This variant was found in 15/121712 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is a common pathogenic variant causing classical PKH, especially in Chinese and/or Taiwanese population with consistent clinical data. The carrier rate of this variant in Han Chinese population was 3.2% in a study that enrolled 212 controls (Zhu_2010). Multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000088786	SCV000708636	pathogenic	not provided	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000632	SCV000814398	pathogenic	Phenylketonuria	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change affects codon 399 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs199475584, gnomAD 0.006%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 24401910, 27264808). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 601). 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.
GeneDx	RCV000088786	SCV002549273	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrates this variant leads to skipping of exon 11 and decreased PAH activity (Chao et al., 2001; Liang et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23225039, 25550961, 19199246, 9949232, 7893121, 24705691, 22333022, 17557229, 20140859, 11214902, 26503515, 16825284, 23932990, 19915519, 14722928, 27173423, 20017307, 29317692, 30747360, 30275481, 27264808, 29499199, 31355225, 1997387, 23271928, 32668217, 25894915, 24401910)
Fulgent Genetics, Fulgent Genetics	RCV000000632	SCV002813445	pathogenic	Phenylketonuria	2022-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000632	SCV004209591	pathogenic	Phenylketonuria	2024-03-05	criteria provided, single submitter	clinical testing
OMIM	RCV000000632	SCV000020782	pathogenic	Phenylketonuria	2001-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088786	SCV000119373	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000632	SCV001132263	pathogenic	Phenylketonuria	2015-03-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000632	SCV002088622	pathogenic	Phenylketonuria	2021-01-13	no assertion criteria provided	clinical testing