chr12-102852924-C-T

Variant names:

• chr12-102852924-C-T
• rs62508694
• NM_000277.3:c.733G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP3 PP4 PM5 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID:26542770) and c.913-7A>G (PMID:29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229722/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.733G>A	p.Val245Met	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.733G>A	p.Val245Met	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.733G>A	p.Val245Met	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.718G>A	p.Val240Met	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.492G>A		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-108G>A		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Nov 10, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID: 26542770) and c.913-7A>G (PMID: 29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4, PP3. -

Dec 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.733G>A (p.Val245Met) results in a conservative amino acid change located in the Aromatic aminoacid monoxygenases, catalytic and oligomerization domain (IPR036329) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251200 control chromosomes. c.733G>A has been reported in the literature in individuals affected with Phenylketonuria or Hyperphenylalaninemia of mild or unreported severity, as a compound heterozygous genotype or heterozygous genotype without reported second variant (e.g. Bayat_2016, Liu_2018, Men_2022, Reblova_2013). These data indicate that the variant may be associated with disease. Multiple different variants affecting the same codon have been classified as pathogenic by our lab (p.Val245Leu, p.Val245Ala), supporting the critical relevance of codon 245 to PAH protein function. One publication reports experimental evidence evaluating an impact on protein function showing the variant results in reduced PAH protein levels in vitro, however, does not allow convincing conclusions about the variant effect (e.g. Zong_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26542770, 28982351, 36787440, 23357515, 29653233). ClinVar contains an entry for this variant (Variation ID: 102809). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAH: PM3:Strong, PM2, PM5, PP4:Moderate, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.8	H;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.91		Gain of methylation at R243 (P = 0.1273);.;
MVP		0.96
MPC		0.24
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508694; hg19: chr12-103246702;