12-102852887-C-T

Variant names:

• chr12-102852887-C-T
• rs62642908
• NM_000277.3:c.770G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4 PM2_Supporting PM5 PM3_Supporting PP3_Strong

This summary comes from the ClinGen Evidence Repository: The c.770G>A variant in PAH is a missense variant predicted to cause substitution of Glycine by Aspartic acid at amino acid 257 (p.Gly257Asp). At least one patient with this variant displayed plasma Phenylalanine > 1200 μmol/L, which is highly specific for PAH deficiency; BH4 deficiency was not reported to be ruled out (PP4, PMID:10693064, 26666653). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.995, which is above the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_strong). Another missense variant c.770G>T, (p.Gly257Val) [ClinVar Variation ID102830] in the same codon has been classified as pathogenic for PAH deficiency by the ClinGen PAH VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4, PM2_supporting, PP3_strong, PM5. (PAH VCEP specifications version 2.0.0; 01/03/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229751/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.91
• Publications: 17 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 9 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.
• PM5: 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.770G>A	p.Gly257Asp	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.770G>A	p.Gly257Asp	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.770G>A	p.Gly257Asp	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.770G>A	p.Gly257Asp	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.770G>A	p.Gly257Asp	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of catalytic residue at G257 (P = 0.0571)
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.019	Neutral
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing

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: rs62642908; hg19: chr12-103246665; COSMIC: COSV100187912; COSMIC: COSV100187912;