Submissions for variant NM_000277.3(PAH):c.1315+4A>G

dbSNP: rs62508649

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672561	SCV001250567	likely pathogenic	Phenylketonuria	2019-11-05	reviewed by expert panel	curation	This c.1315+4A>G variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in four patients diagnosed with PAH deficiency (PMID: 16256386, 28982351, 25456745, 23932990). This variant is present in the population database gnomAD at a frequency below 0.0002. According to in silico splicing predictions, this alteration is probably damaging (TraP score 0.992). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3.
Counsyl	RCV000672561	SCV000797674	likely pathogenic	Phenylketonuria	2018-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672561	SCV000961175	pathogenic	Phenylketonuria	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62508649, gnomAD 0.006%). This variant has been observed in individual(s) with phenylalaninehydroxylase deficiency (PMID: 16256386, 23932990). This variant is also known as IVS12+4A>G. ClinVar contains an entry for this variant (Variation ID: 102589). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	RCV000672561	SCV004209628	pathogenic	Phenylketonuria	2023-07-28	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088828	SCV000119420	not provided	not provided		no assertion provided	not provided