Submissions for variant NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)

dbSNP: rs62642906

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000153638	SCV000852108	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PM3, PP4).
Eurofins Ntd Llc (ga)	RCV000088944	SCV000203188	pathogenic	not provided	2014-04-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000153638	SCV000221085	likely pathogenic	Phenylketonuria	2015-01-26	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000153638	SCV000754077	pathogenic	Phenylketonuria	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser16*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62642906, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with hyperphenylalaninemia and phenylketonuria (PMID: 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415). This variant is also known as c.44_45delTC, p.Ser16fs. ClinVar contains an entry for this variant (Variation ID: 102696). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153638	SCV001362289	pathogenic	Phenylketonuria	2019-03-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.47_48delCT (p.Ser16X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.165delT, p.Phe55fsX6; c.331C>T, p.Arg111X; c.556delA, p.Thr186fsX9). The variant allele was found at a frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Aldamiz-Echevarria_2016, Ramus_1995, Tao_2015, Trunzo_2015, Wang_2017). These data indicate that the variant is very likely to be associated with disease. In vitro expression experiment reports that PAH residual activity for this variant effect results in <10% of normal activity (Aldamiz-Echevarria_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV000153638	SCV002107119	pathogenic	Phenylketonuria	2022-03-05	criteria provided, single submitter	clinical testing	The c.47_48delCT;p.(Ser16*) variant creates a premature translational stop signal in the PAH gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 10269; PMID: 8535445; PMID: 10394930; PMID: 16198137; PMID: 17096675; PMID: 21147011; PMID: 21890392; PMID: 263224156) - PS4. This variant is not present in population databases (rs62642906- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ser16*) was detected in trans with a pathogenic variant (PMID:8535445) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
GeneDx	RCV000088944	SCV004014197	pathogenic	not provided	2023-07-16	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21890392, 12655550, 12655553, 23357515, 8535445, 19444284, 16879198, 23430918, 17935162, 23430547, 21147011, 19062537, 10394930, 31589614, 29499199, 32668217, 35405047)
Baylor Genetics	RCV000153638	SCV004201315	pathogenic	Phenylketonuria	2023-12-26	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000153638	SCV005418464	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_VeryStrong
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088944	SCV000119545	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000153638	SCV001459232	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000153638	SCV004099308	pathogenic	Phenylketonuria	2023-10-30	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000153638	SCV004800848	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	PVS1+PM2+PM3_S+PP4_M