rs62642913

Variant names:

• chr12-102846935-G-A
• rs62642913
• NM_000277.3:c.929C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102846935-G-A
• chr12-102846935-G-C
• chr12-102846935-G-T

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM3 PM2_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000277.1(PAH):c.929C>T (p.Ser310Phe) variant is a missense variant in exon 9/13 of PAH. The variant has been found to result in <1% of wild-type PAH enzyme activity in a standard cDNA and an Intinc system (PMID:18590700) (PS3_supporting). It has been found in at least 8 PKU patients, including among those whom BH4 deficiency was excluding and in trans with other Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4.75 points); PP4_Moderate). It has been found in 2 alleles in a survey of German PKU patients (PMID:12655553); in trans with the c.442-1G>A (Pathogenic in ClinVar and by ClinGen PAH VCEP) variant in a Korean patient with moderate PKU (plasma Phe 600-1200 umol/L) with BH4 deficiency excluded by urinary pterin analysis and dihydropteridine reductase (DHPR) assay (PMID:15503242). It has been found in as a homozygous variant in a Syrian patient with classic PKU (plasma Phe 1262 umol/L) (PMID:23856132). It has been found in two Chinese patients with classic PKU and BH4 deficiency excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes: one harbored it in trans with the p.R111* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) and one in trans with the p.Y356* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) (PMID:30050108). It has been found in a Chinese patient with mild hyperphenylalanemia (plasma Phe 120-360 umol/L) in trans with p.R241C (Pathogenic in ClinVar and by ClinGen PAH VCEP); BH4 deficiency was excluded (PMID:25894915). It has been found in trans with p.F302V (unclassified) in a Chinese patient with mild PKU (plasma Phe 360–1200 μmol/L) and BH4 deficiency excluded (PMID:30459323). It has been reported in trans with c.1066-3C>T (Pathogenic/Likely Pathogenic in ClinVar and by ClinGen PAH VCEP)in a PKU patient (PMID:23430918). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.993) (PP3).Classification: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229855/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 9.60
• Publications: 11 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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 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.929C>T	p.Ser310Phe	missense	Exon 9 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.929C>T	p.Ser310Phe	missense	Exon 10 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.929C>T	p.Ser310Phe	missense	Exon 9 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1028C>T	p.Ser343Phe	missense	Exon 10 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.929C>T	p.Ser310Phe	missense	Exon 9 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Phenylketonuria (5)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of disorder (P = 0.0509)
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs62642913; hg19: chr12-103240713;