rs62508728

chr12-102855225-T-C

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.617A>G(p.Tyr206Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y206D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1 O:1
• Conservation: PhyloP100: 8.02

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-102855225-T-C is Pathogenic according to our data. Variant chr12-102855225-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102762.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102855225-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.617A>G	p.Tyr206Cys	missense_variant	6/13	ENST00000553106.6
PAH	NM_001354304.2	c.617A>G	p.Tyr206Cys	missense_variant	7/14
PAH	XM_017019370.2	c.617A>G	p.Tyr206Cys	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.617A>G	p.Tyr206Cys	missense_variant	6/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.713A>G		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.602A>G	p.Tyr201Cys	missense_variant	7/14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 12, 2022	The NM_000277.3(PAH):c.617A>G (p.Tyr206Cys) missense variant has been reported in 1 patient with mild phenylketonuria (Phe = 914 umol/liter, BH4 deficiency excluded) (PP4_moderate; PMID: 29499199). This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, Polyphen2, Mutation Taster. REVEL= 0.96 (PP3). This variant has been detected with pathogenic variants: p.Y204C (PMID: 16256386) and R241C (PMID: 26322415) (PM3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM3, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 10, 2017	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.93	P;.
Vest4		0.87
MutPred		0.95		Loss of stability (P = 0.1178);.;
MVP		0.99
MPC		0.16
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508728; hg19: chr12-103249003;