rs199475679

chr12-102866599-C-Gchr12-102866599-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000277.3(PAH):c.506G>C(p.Arg169Pro) 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 Uncertain significance (★★★). 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: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 2.06

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 10 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, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.506G>C	p.Arg169Pro	missense_variant	5/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.807+1372C>G		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.506G>C	p.Arg169Pro	missense_variant	6/14
PAH	XM_017019370.2	c.506G>C	p.Arg169Pro	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.506G>C	p.Arg169Pro	missense_variant	5/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.602G>C		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.491G>C	p.Arg164Pro	missense_variant	6/14	5
PAH	ENST00000551988.5	n.530+10863G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Center, Academic Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi	Oct 18, 2017	The mutation has been detected in compound heterozygous state with another pathogenic mutation (c.506G>C) in a 5 years old girl affected with PKU and was found in heterozygous in her father. -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 26, 2021	The c.506G>C (p.Arg169Pro) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 446524); no further information is provided. At the time of review, the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent in gnomAD (PM2). Other missense variants at this site are pathogenic/likely pathogenic – p.Arg169Ser (variant ID 932262), p.Arg169His (variant ID 102706), p.Arg169Gly (variant ID 551103), and p.Arg169Cys (variant ID 125436) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.80		Loss of MoRF binding (P = 0.0059);.;
MVP		0.98
MPC		0.23
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.97

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: rs199475679; hg19: chr12-103260377;