Submissions for variant NM_000277.3(PAH):c.806del (p.Ile269fs)

gnomAD frequency: 0.00002  dbSNP: rs62508687

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000153633	SCV000852125	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. gnomAD MAF=0.00007.; PP4: Detected in a PKU patient. BH4 deficiency not assessed. (PMID:9012412). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4).
Eurofins Ntd Llc (ga)	RCV000089103	SCV000203181	pathogenic	not provided	2017-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000153633	SCV000629216	pathogenic	Phenylketonuria	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile269Thrfs*72) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62508687, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 9012412, 17502162, 18937047, 23430918, 24368688). This variant is also known as 1269fsdelT. ClinVar contains an entry for this variant (Variation ID: 102844). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153633	SCV001361063	pathogenic	Phenylketonuria	2019-06-06	criteria provided, single submitter	clinical testing	Variant summary: PAH c.806delT (p.Ile269ThrfsX72) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251364 control chromosomes. c.806delT has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tyfield_1997, Dombrowolski_2007, Sarkissian_2011, Ho_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen) classify the variant as pathogenic three times and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000153633	SCV004209657	pathogenic	Phenylketonuria	2023-11-21	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089103	SCV000119710	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000153633	SCV000485936	likely pathogenic	Phenylketonuria	2016-03-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000153633	SCV001453103	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing