Submissions for variant NM_000277.3(PAH):c.441+6T>C

dbSNP: rs199475698

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001789757	SCV002032213	uncertain significance	Phenylketonuria	2020-07-02	reviewed by expert panel	curation	The c.441+6T>C variant in PAH has been reported before in the homozygous state in a patient with PKU and BH4 deficiency excluded (PMID: 21147011). It is absent in population databases. Multiple lines of computational evidence support a deleterious effect (MaxENT, Splice AI, dbsSNV Ada, and RF). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001789757	SCV002280079	pathogenic	Phenylketonuria	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 32668217; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102675). 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. This variant disrupts the c.441+6T nucleotide in the PAH gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22526846, 23357515). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088923	SCV000119522	not provided	not provided		no assertion provided	not provided