12-102855148-G-C

Position:

• chr12-102855148-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000277.3(PAH):​c.694C>G​(p.Gln232Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Q232L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 4.13

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 12 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-102855148-G-C is Pathogenic according to our data. Variant chr12-102855148-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 619160.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.694C>G	p.Gln232Glu	missense_variant	6/13	ENST00000553106.6
PAH	NM_001354304.2	c.694C>G	p.Gln232Glu	missense_variant	7/14
PAH	XM_017019370.2	c.694C>G	p.Gln232Glu	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.694C>G	p.Gln232Glu	missense_variant	6/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.790C>G		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.679C>G	p.Gln227Glu	missense_variant	7/14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic: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

Dec 10, 2018

The c.694C>G (p.Gln232Glu) variant in PAH has not been reported in the literature in individuals with PKU. It has been co-expressed with p.E178G and showed 55.0% enzyme activity. PMID: 26803807. BioPKU reports a 42% enzyme activity for this variant (PS3; PMID: 12501224). This variant is absent in population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.22
DEOGEN2	Uncertain	0.63	D;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	0.26	N;.
MutationTaster	Benign	0.83	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.97	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;.
Vest4		0.42
MutPred		0.42		Gain of disorder (P = 0.1708);.;
MVP		0.92
MPC		0.037
ClinPred		0.39	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.86

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: rs62507348; hg19: chr12-103248926;