Submissions for variant NM_000277.3(PAH):c.310_318del (p.Ala104_Val106del)

gnomAD frequency: 0.00001  dbSNP: rs398123291

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000721174	SCV000852090	uncertain significance	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4).
Eurofins Ntd Llc (ga)	RCV000078519	SCV000110375	uncertain significance	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000721174	SCV002950218	pathogenic	Phenylketonuria	2023-10-15	criteria provided, single submitter	clinical testing	This variant, c.310_318del, results in the deletion of 3 amino acid(s) of the PAH protein (p.Ala104_Val106del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123291, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 92740). This variant disrupts a region of the PAH protein in which other variant(s) (p.Ala104Asp) have been determined to be pathogenic (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). 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.