Submissions for variant NM_000277.3(PAH):c.1024del (p.Ala342fs)

dbSNP: rs63581460

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000412182	SCV000852167	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PVS1: Frameshift variant; PP4_Moderate: Reported in patients with PAH deficiency. Bh4 defects excluded. (PMID:9634518). 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: (PM2, PVS1, PP4_Moderate).
GeneDx	RCV000088706	SCV000329861	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing	The c.1024delG pathogenic variant has been reported previously in association with PKU (Guldberg et al., 1998; Liu et al., 2015). The deletion causes a frameshift starting with codon Alanine 342, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Ala342HisfsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Counsyl	RCV000412182	SCV000486461	pathogenic	Phenylketonuria	2016-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412182	SCV000917918	pathogenic	Phenylketonuria	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1024delG (p.Ala342HisfsX58) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251246 control chromosomes. c.1024delG has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldber_1998, Li_2015, Zhu_2013, Liu_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. The following publications have been ascertained in the context of this evaluation (PMID: 9634518, 26503515, 23932990, 26600521). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412182	SCV002246006	pathogenic	Phenylketonuria	2021-08-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with phenylketonuria (PMID: 26503515, 26600521). This variant is also known as c.1023del (p.A342Hfs*59). ClinVar contains an entry for this variant (Variation ID: 102475). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala342Hisfs*58) 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).
Baylor Genetics	RCV000412182	SCV004209672	pathogenic	Phenylketonuria	2023-05-01	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088706	SCV000119286	not provided	not provided		no assertion provided	not provided