Submissions for variant NM_000277.3(PAH):c.125AAG[2] (p.Glu44del)

dbSNP: rs199475628

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000666206	SCV004015308	likely pathogenic	Phenylketonuria	2023-07-23	reviewed by expert panel	curation	The NM_000277.3:c.125AAG[2] variant in PAH is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region (p.Glu44del) (PM4). This variant has been detected in at least 3 unrelated individuals with PAH deficiency (PMID: 28982351, PMID: 26600521, PMID: 9012412). Of these individuals, one was a compound heterozygote for the variant and a pathogenic variant, p.Arg408Trp, in trans (phase confirmed by parental testing) (PMID: 26600521), and one was a compound heterozygote for the variant and a likely pathogenic variant, p.Met276Arg, in trans (phase confirmed by parental testing) (PMID: 28982351) (2pts total, PM3_Strong). These two individuals had plasma phenylalanine >120 μmol/L and exclusion of a defect of BH4 cofactor metabolism (PMID: 28982351, PMID: 26600521). These two individuals had plasma phenylalanine >120 μmol/L and exclusion of a defect of BH4 cofactor metabolism (PMID: 28982351, PMID: 26600521). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000096 (1/10368 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 102594, 1 star review status) with one submitter classifying the variant as likely pathogenic and 3 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic 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, PM3_Strong, PM4, PP4_Moderate.
Counsyl	RCV000666206	SCV000790459	uncertain significance	Phenylketonuria	2017-03-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000666206	SCV000914561	uncertain significance	Phenylketonuria	2017-04-28	criteria provided, single submitter	clinical testing	The PAH c.131_133delAAG (p.Glu44del) variant is an in-frame deletion variant that has been reported in two studies, where it was found in a total of three cases of confirmed or suspected phenylalanine hydroxylase (PAH) deficiency, including in a compound heterozygous state in two and in a heterozygous state in one (Liu et al. 2015; Tyfield et al. 1997). The first compound heterozygote had a confirmed diagnosis of PAH deficiency and carried the p.Glu44del variant in trans with a known pathogenic missense variant. The second compound heterozygote was a fetus with no confirmed diagnosis and carried the p.Glu44del variant in trans with the same pathogenic missense variant as the first individual (Liu et al. 2015). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium despite good sequence coverage of the region. Based on the limited evidence, the p.Glu44del variant is classified as a variant of uncertain significance but suspicious for pathogenicity for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666206	SCV002500322	likely pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: PAH c.131_133delAAG (p.Glu44del) results in an in-frame deletion that is predicted to remove 1 amino acid from the ACT domain (IPR002912) of the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 251414 control chromosomes (gnomAD). c.131_133delAAG has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), including at least two confirmed compound heterozygous patients carrying pathogenic/likely pathogenic variants in trans (Tyfield_1997, Liu_2015, Liu_2017, Wang_218). 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: 28982351, 26600521, 9012412, 29499199). ClinVar contains an entry for this variant (Variation ID: 102594). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666206	SCV002951832	uncertain significance	Phenylketonuria	2022-06-28	criteria provided, single submitter	clinical testing	This variant, c.131_133del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Glu44del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199475628, gnomAD 0.005%). This variant has been observed in individual(s) with phenylketonuria (PMID: 9012412). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102594). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000666206	SCV004847370	likely pathogenic	Phenylketonuria	2023-11-13	criteria provided, single submitter	clinical testing	The p.Glu44del variant in PAH has been reported in the compound heterozygous state with another pathogenic variant in PAH in at least 2 individuals with phenylketonuria (PKU) who had elevated plasma phenylalanine and exclusion of a defect of BH4 cofactor metabolism (Liu 2015 PMID: 26600521, Liu 2017 PMID: 28982351). This variant was also identified in at least 2 other individuals with PAH but there was no additional information on whether there were any additional variants identified or whether they were in cis or trans (Tyfield 1997 PMID: 9012412, Wang 2018 PMID: 29499199). It has also been identified in 0.01% (8/68018) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), at a frequency that is low enough to be consistent with a recessive carrier frequency. This variant is a deletion of 1 amino acid at position 44 and is not predicted to alter the protein reading-frame. This variant was classified as Likely Pathogenic on Jul 23, 2023 by the ClinGen-approved PAH Variant Curation expert panel (Variation ID 102594). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive PKU. ACMG/AMP Criteria applied: PM3_Strong, PM4_Supporting, PP4, PM2_Supporting.
Baylor Genetics	RCV000666206	SCV005053814	likely pathogenic	Phenylketonuria	2024-03-15	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088833	SCV000119417	not provided	not provided		flagged submission	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088833	SCV000119425	not provided	not provided		no assertion provided	not provided