12-102866600-G-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.505C>G(p.Arg169Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 1.07

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr12-102866600-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 125436.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 12-102866600-G-C is Pathogenic according to our data. Variant chr12-102866600-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 551103.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.505C>G	p.Arg169Gly	missense_variant	5/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.807+1373G>C		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.505C>G	p.Arg169Gly	missense_variant	6/14
PAH	XM_017019370.2	c.505C>G	p.Arg169Gly	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.505C>G	p.Arg169Gly	missense_variant	5/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.601C>G		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.490C>G	p.Arg164Gly	missense_variant	6/14	5
PAH	ENST00000551988.5	n.530+10862C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Feb 12, 2021	The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID: 30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;.
Vest4		0.88
MutPred		0.81		Loss of MoRF binding (P = 0.0202);.;
MVP		0.96
MPC		0.14
ClinPred		1.0	D
GERP RS		-0.060
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.86
gMVP		0.93

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: rs281865440; hg19: chr12-103260378;