NM_000277.3:c.940C>A

Variant names:

• chr12-102846924-G-T
• rs199475650
• NM_000277.3:c.940C>A

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PM2_Supporting PP4_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000277.1(PAH):c.940C>A (p.Pro314Thr) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 25% of wild-type PAH enzyme activity in a standard cDNA system and 19% of wild-type PAH enzyme activity in an Intinc system (PMID:18590700) (PS3_supporting). It has been reported in at least five PKU patients, including those with BH4 deficiency excluded and in trans with Pathogenic variants (PM3_VeryStrong (4.25 points); PP4_Moderate). It has been previously reported in a Taiwanese proband in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) with mild hyperphenylalanemia and BH4 deficiency excluded by urinary pterins, dihydropteridine reductase activity in erythrocytes, and sequencing of the genes in the BH4 cofactor metabolism pathway (PMID:14722928). It has also been found in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) in a Chinese patient with classic PKU (plasma Phe 1230 umol/L) and BH4 deficiency excluded (PMID:28982351). It has been noted in a Chinese patient with plasma Phe 184 umol/L and BH4 deficiency excluded in trans with a deletion of exons 1-3 (unclassified) (PMID:29499199). It has been also noted in a Chinese patient with mild hyperphenylalanemia (plasma Phe 148 umol/L) in trans with the p.S70del (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant and in trans with the p.R243Q (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant in a patient with classic PKU (plasma Phe 1561 umol/L); BH4 deficiency was excluded in both cases (PMID:30459323). Another missense variant at the same site, c.941C>A (p.P314H) is classified as Pathogenic/Likely Pathogenic in ClinVar (ID 102907) (PM5). Two heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global frequency of 0.00000796 and a maximum population frequency of 0.000109 (South Asian), under the 0.0002 frequency cutoff for use of PM2 (PM2_supporting). The variant is predicted damaging by multiple in-silico predictors, including REVEL (REVEL score 0.867), but tolerated by SIFT; thus, PP3 is not met. Classification: PathogenicSupporting Criteria: PS3_supporting; PM3_VeryStrong; PM2_supporting; PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA229863/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 5.49
• Publications: 10 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: Pathogenic. The variant received 6 ACMG points.

• PS3: 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.940C>A	p.Pro314Thr	missense	Exon 9 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.940C>A	p.Pro314Thr	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.940C>A	p.Pro314Thr	missense	Exon 9 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1039C>A	p.Pro347Thr	missense	Exon 10 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.940C>A	p.Pro314Thr	missense	Exon 9 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251290 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111690

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Phenylketonuria (6)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.87
Sift	Benign	0.099	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.89		Gain of catalytic residue at P314 (P = 0.0362)
MVP		0.98
MPC		0.24
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.90
Mutation Taster		=1/99	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: rs199475650; hg19: chr12-103240702;