rs199475657

Variant names:

• chr12-102852934-GC-G
• rs199475657
• NM_000277.3:c.722delG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PVS1 PP4_Moderate PM3

This summary comes from the ClinGen Evidence Repository: The PAH variant c.722del (p.Arg241fs) is a null variant (frameshift indel) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The mRNA transcript is predicted to undergo NMD.The PAH variant c.722del (p.Arg241fs) was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10–20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID:26322415).The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PMID:26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612)(PMID:30459323). PM3_Very Strong (6.75).The variant c.722del (p.Arg241fs) is absent from the gnomAD, and ExAC population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong (6.75), PVS1, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229717/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 4.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.722delG	p.Arg241ProfsTer100	frameshift_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.722delG	p.Arg241ProfsTer100	frameshift_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.722delG	p.Arg241ProfsTer100	frameshift_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.707delG	p.Arg236ProfsTer100	frameshift_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.481delG		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-119delG		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Jun 20, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.722delG (p.Arg241ProfsX100) 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 251030 control chromosomes (gnomAD). c.722delG has been reported in the literature in several Chinese individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Tao_2015, Li_2018, Wang_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2; including the Expert Panel) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg241Profs*100) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 12905706, 25550961, 29499199). This variant is also known as p.Arg241fs or p.Arg241fsX5. ClinVar contains an entry for this variant (Variation ID: 102806). For these reasons, this variant has been classified as Pathogenic. -

May 09, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The PAH variant c.722del (p.Arg241fs) is a null variant (frameshift indel) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The mRNA transcript is predicted to undergo NMD. The PAH variant c.722del (p.Arg241fs) was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10-20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PMID: 26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612)(PMID: 30459323). PM3_Very Strong (6.75). The variant c.722del (p.Arg241fs) is absent from the gnomAD, and ExAC population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong (6.75), PVS1, PP4_Moderate. -

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PM3_VeryStrong+PP4_Moderate -

Aug 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Other:1

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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs199475657; hg19: chr12-103246712;