rs199475657

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM3 PM2 PVS1 PP4_Moderate

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:7 O:1
• Conservation: PhyloP100: 4.91
• Publications: 14 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 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.722delG	p.Arg241ProfsTer100	frameshift	Exon 7 of 13	NP_000268.1
	PAH	NM_001354304.2		c.722delG	p.Arg241ProfsTer100	frameshift	Exon 8 of 14	NP_001341233.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.722delG	p.Arg241ProfsTer100	frameshift	Exon 7 of 13	ENSP00000448059.1
	PAH	ENST00000906695.1		c.722delG	p.Arg241ProfsTer59	frameshift	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.722delG	p.Arg241ProfsTer91	frameshift	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Phenylketonuria (7)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199475657; hg19: chr12-103246712;