Submissions for variant NM_000277.3(PAH):c.648C>G (p.Tyr216Ter)

dbSNP: rs62509013

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000179283	SCV001448240	pathogenic	Phenylketonuria	2020-10-30	reviewed by expert panel	curation	The c.648C>G (p.Tyr216Ter) variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Glu280Lys (ClinVar 580). This variant is absent from 1000G, ESP, and gnomAD databases. This variant creates a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting.
Eurofins Ntd Llc (ga)	RCV000089019	SCV000231508	pathogenic	not provided	2014-11-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179283	SCV000813184	pathogenic	Phenylketonuria	2023-09-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102769). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 17502162, 26666653). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr216*) 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).
GeneDx	RCV000089019	SCV001167689	pathogenic	not provided	2023-05-20	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17502162, 32668217, 31923802, 26666653, 23430918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179283	SCV001361065	pathogenic	Phenylketonuria	2019-06-06	criteria provided, single submitter	clinical testing	Variant summary: PAH c.648C>G (p.Tyr216X) 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 251324 control chromosomes (gnomAD). c.648C>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tyfield_1997, Dombrowolski_2007, Sarkissian_2011, Jeannesson-Thivisol_2015). 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000179283	SCV004209677	pathogenic	Phenylketonuria	2023-04-25	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089019	SCV000119624	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000179283	SCV002088652	pathogenic	Phenylketonuria	2020-12-31	no assertion criteria provided	clinical testing