chr12-102852856-C-G

Variant names:

• chr12-102852856-C-G
• rs199475675
• NM_000277.3:c.801G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PP3 PM3 PM2

This summary comes from the ClinGen Evidence Repository: The c.801G>C (p.Gln267His) variant in PAH has been reported in 1 Chinese patient with classical PKU. BH4 deficiencies were not assessed. PMID:16256386, 19915519. It was detected with a known pathogenic variant p.R252Q. PMID:16256386. It is absent from population databases. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.952. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229771/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 2.25
• Publications: 4 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), ClinGen, Myriad Women’s Health, G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.801G>C	p.Gln267His	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.801G>C	p.Gln267His	missense	Exon 8 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.801G>C	p.Gln267His	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.801G>C	p.Gln267His	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.801G>C	p.Gln267His	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of sheet (P = 0.0827)
MVP		0.99
MPC		0.24
ClinPred		1.0	D
GERP RS		3.0
PromoterAI		0.028	Neutral
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199475675; hg19: chr12-103246634;