Submissions for variant NM_000277.3(PAH):c.353-7_353-5dup

dbSNP: rs1452763334

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668138	SCV004015313	uncertain significance	Phenylketonuria	2023-07-23	reviewed by expert panel	curation	The NM_000277.3:c.353-7_353-5dup variant in PAH is an intronic variant affecting 3 nucleotides in intron 3. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.28 for acceptor loss which is neither above nor below the thresholds predicting an impact (>0.5) or no impact (<0.2) on PAH splicing. There is a ClinVar entry for this variant (Variation ID: 552806, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting.
Counsyl	RCV000668138	SCV000792689	uncertain significance	Phenylketonuria	2017-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668138	SCV001607634	likely benign	Phenylketonuria	2023-10-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668138	SCV001467000	uncertain significance	Phenylketonuria	2020-04-17	no assertion criteria provided	clinical testing