Submissions for variant NM_000277.3(PAH):c.1066-14C>G

dbSNP: rs62507334

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001375895	SCV001572858	likely pathogenic	Phenylketonuria	2020-12-11	reviewed by expert panel	curation	The c.1066-14C>G PAH variant has been reported in 1 Chinese patient with PAH deficiency (Phe =512μmol/L) detected with the pathogenic PAH variant c.1222C>T (PMID: 29499199). A defect in BH4 metabolism was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant is absent from population databases gnomAD, 1000 Genomes and ESP. Splicing prediction algorithms predict this variant to be probably damaging. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PP3, PM3_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001375895	SCV003441215	pathogenic	Phenylketonuria	2022-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 102508). This variant is also known as IVS10-14C>G. This variant has been observed in individual(s) with PAH-related conditions (PMID: 17502162, 29499199, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375895	SCV004122166	pathogenic	Phenylketonuria	2023-10-26	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1066-14C>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 3' acceptor site. Two predict the variant weakens a canonical 3' acceptor site. The variant was absent in 250464 control chromosomes (gnomAD). c.1066-14C>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Shirzadeh_2018, Zhu_2013, Lee_2008, Dobrowolski_2007, Kimura_2001). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30159852, 17502162, 18985011, 11207989, 23932990). Two submitters (including ClinGen PAH Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001375895	SCV004209681	pathogenic	Phenylketonuria	2023-04-14	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088739	SCV000119322	not provided	not provided		no assertion provided	not provided