Submissions for variant NM_000277.3(PAH):c.169_171del

dbSNP: rs199475665

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000993610	SCV001146716	likely pathogenic	Phenylketonuria	2019-08-26	reviewed by expert panel	curation	The c.169_171del in-frame deletion variant has been identified in at least 2 probands with phenotypes of mild to classic PKU (PMIDs: 18299955, 22106832). It has been detected in trans with pathogenic variants Ala403Val (PMID: 18299955) and c.1066-11G>A (PMID: 22106832). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PM4, PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000993610	SCV002228241	pathogenic	Phenylketonuria	2022-01-18	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 18299955, 22106832, 32668217, 32905092). This variant, c.169_171del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Glu57del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant is also known as IVS2 -2 del. ClinVar contains an entry for this variant (Variation ID: 102613). This variant disrupts a region of the PAH protein in which other variant(s) (p.Glu57Lys) have been observed in individuals with PAH-related conditions (PMID: 21147011). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000993610	SCV004209711	pathogenic	Phenylketonuria	2023-01-18	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088855	SCV000119450	not provided	not provided		no assertion provided	not provided