rs62508588

chr12-102852929-C-Achr12-102852929-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):c.728G>T(p.Arg243Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243Q) has been classified as Likely pathogenic.

• 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: 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 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102852929-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 12-102852929-C-A is Pathogenic according to our data. Variant chr12-102852929-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102808.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102852929-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.728G>T	p.Arg243Leu	missense_variant	7/13	ENST00000553106.6
PAH	NM_001354304.2	c.728G>T	p.Arg243Leu	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.728G>T	p.Arg243Leu	missense_variant	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.713G>T	p.Arg238Leu	missense_variant	8/14	5
PAH	ENST00000549247.6	n.487G>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Feb 14, 2021

The c.728G>T (p.Arg243Leu) variant in PAH has been reported in 1 individual with PKU detected with pathogenic variant p.R261Q (P 9 submitters) PMID: 12655553, 20217238. This variant is absent in population databases. Computational evidence supports a deleterious effect. Another missense change at the same amino acid,p .Arg243Gln, is pathogenic in ClinVar by multiple submitters (variation ID 591). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PM5, PP3. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.95		Loss of methylation at R243 (P = 0.0151);.;
MVP		0.98
MPC		0.26
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62508588; hg19: chr12-103246707;