Submissions for variant NM_000277.3(PAH):c.1199+1G>C

dbSNP: rs62509015

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169248	SCV000852176	pathogenic	Phenylketonuria	2018-08-27	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. 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, PM3, PP4_Moderate, PVS1).
Counsyl	RCV000169248	SCV000220530	likely pathogenic	Phenylketonuria	2014-07-19	criteria provided, single submitter	literature only
GeneDx	RCV000088791	SCV000239091	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing	The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys the canonical splice donor site in intron 11, and is expected to cause abnormal gene splicing. The variant is found in PAH panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169248	SCV000629177	pathogenic	Phenylketonuria	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62509015, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 20187763, 22526846, 22763404, 23856132, 24301756, 26351554, 26413448). This variant is also known as IVS11+1G>C. ClinVar contains an entry for this variant (Variation ID: 102557). 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.
Baylor Genetics	RCV000169248	SCV001163713	pathogenic	Phenylketonuria	2023-11-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169248	SCV001362290	pathogenic	Phenylketonuria	2019-02-28	criteria provided, single submitter	clinical testing	Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246046 control chromosomes (gnomAD) and as been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Zare-Karizi_2011, Dobrowolski_2011, Jeannesson-Thivisol_2015, Liu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dobrowolski_2011), however, does not allow convincing conclusions about the variant effect. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000169248	SCV002581544	pathogenic	Phenylketonuria	2022-03-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169248	SCV002790388	pathogenic	Phenylketonuria	2021-11-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000088791	SCV004702167	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PVS1, PM2, PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088791	SCV000119378	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169248	SCV001463115	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing