rs199475628

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000277.3(PAH):c.131_133del(p.Glu44del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000861 in 1,613,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

PAH
NM_000277.3 inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:3O:2

Conservation

PhyloP100: 5.10

Variant links:

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000277.3

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000277.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 12-102912825-ACTT-A is Pathogenic according to our data. Variant chr12-102912825-ACTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102594.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PAH	NM_000277.3 linkuse as main transcript	c.131_133del	p.Glu44del	inframe_deletion	2/13	ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.131_133del	p.Glu44del	inframe_deletion	3/14
PAH	XM_017019370.2 linkuse as main transcript	c.131_133del	p.Glu44del	inframe_deletion	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.131_133del	p.Glu44del	inframe_deletion	2/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251414

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461268

Hom.:

AF XY:

0.0000922

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000491

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:3Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:3Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 13, 2023	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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 23, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 28, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not provided

Other:2

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
not provided, flagged submission	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over