Submissions for variant NM_000277.3(PAH):c.169-13T>G

gnomAD frequency: 0.00001  dbSNP: rs62507341

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000778351	SCV002032195	likely pathogenic	Phenylketonuria	2020-08-17	reviewed by expert panel	curation	The c.169-13T>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 9521426, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with pathogenic variants: IVS10-11G>A (PMID: 21147011); p.L213P (PMID: 9521426); p.R158Q (PMID: 12640344); p.Y356X (c.1068C > G in 1 patient and c.1068C > A in 1 patient, PMID: 30389586). Computational evidence support a deleterious effect on splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.
GeneDx	RCV000088853	SCV000617704	likely pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9521426, 12655550, 34426522, 10394930, 32668217)
Illumina Laboratory Services, Illumina	RCV000778351	SCV000914559	pathogenic	Phenylketonuria	2018-12-06	criteria provided, single submitter	clinical testing	The PAH c.169-13T>G intron variant has been reported in five studies and is found in a total of seven individuals with phenylalanine hydroxylase deficiency including in six in a compound heterozygous state and in one in a heterozygous state where the second variant could not be identified (Bosco et al. 1998; Kasnauskiene et al. 2003; Kasnauskiene et al. 2008; Zurflüh et al. 2008; Esfahani et al. 2018). Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. This is based on one allele only in a region with good coverage, suggesting that this is a rare variant. Authors predict this variant may activate a cryptic splice site, but no supporting evidence is provided (Bosco et al. 1998). Based on the clinical evidence, the c.169-13T>G variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778351	SCV001590611	pathogenic	Phenylketonuria	2023-06-02	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 102611). This variant is also known as IVS2-13T>G. This variant has been observed in individual(s) with phenylketonuria (PMID: 9521426, 30389586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs62507341, gnomAD 0.0009%). This sequence change falls in intron 2 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088853	SCV000119448	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000778351	SCV002088673	pathogenic	Phenylketonuria	2017-09-20	no assertion criteria provided	clinical testing