Submissions for variant NM_000277.3(PAH):c.913-7A>G

gnomAD frequency: 0.00001  dbSNP: rs62517165

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000589029	SCV001370819	likely pathogenic	Phenylketonuria	2020-02-16	reviewed by expert panel	curation	The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589029	SCV000696472	pathogenic	Phenylketonuria	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, the variant was classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000089156	SCV000703341	pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000589029	SCV000893938	likely pathogenic	Phenylketonuria	2021-07-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089156	SCV001470580	pathogenic	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low nucleotide conservation. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589029	SCV001580108	pathogenic	Phenylketonuria	2024-04-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62517165, gnomAD 0.003%). This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 26600521, 29499199, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G. ClinVar contains an entry for this variant (Variation ID: 102894). 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	RCV000589029	SCV004209594	pathogenic	Phenylketonuria	2023-09-07	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089156	SCV000119770	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000589029	SCV000791679	likely pathogenic	Phenylketonuria	2017-05-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000589029	SCV001463132	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing