chr12-102912825-ACTT-A

Variant names:

• chr12-102912825-ACTT-A
• rs199475628
• NM_000277.3:c.131_133delAAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000277.3(PAH):​c.131_133delAAG​(p.Glu44del) variant causes a disruptive 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 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2 O:2
• Conservation: PhyloP100: 5.10
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 VariationId is 102594.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.131_133delAAG	p.Glu44del	disruptive_inframe_deletion	Exon 2 of 13	NP_000268.1
	PAH	NM_001354304.2		c.131_133delAAG	p.Glu44del	disruptive_inframe_deletion	Exon 3 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.131_133delAAG	p.Glu44del	disruptive_inframe_deletion	Exon 2 of 13	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.227_229delAAG		non_coding_transcript_exon	Exon 2 of 6
	PAH	ENST00000307000.7	TSL:5	c.116_118delAAG	p.Glu39del	disruptive_inframe_deletion	Exon 3 of 14	ENSP00000303500.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152124 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251414 AF XY: 0.0000294

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 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.: 0 AF XY: 0.0000922 AC XY: 67 AN XY: 726978

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111528

Other (OTH) AF: 0.000133 AC: 8 AN: 60376

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5 Uncertain:2

Jun 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 21, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jan 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jul 25, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 23, 2023

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: 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.

Nov 13, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 15, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Other:2

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs199475628; hg19: chr12-103306603;