12-102855151-A-G

Variant names:

• chr12-102855151-A-G
• rs5030845
• NM_000277.3:c.691T>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):​c.691T>C​(p.Ser231Pro) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S231F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.32
• Publications: 11 publications found

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]

PAH Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr12-102855150-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 102787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 440 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: -0.64755 (below the threshold of 3.09). Trascript score misZ: -0.0084567 (below the threshold of 3.09). GenCC associations: The gene is linked to phenylketonuria, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, maternal phenylketonuria, classic phenylketonuria, mild phenylketonuria, mild hyperphenylalaninemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 12-102855151-A-G is Pathogenic according to our data. Variant chr12-102855151-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 102786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.691T>C	p.Ser231Pro	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.691T>C	p.Ser231Pro	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2	c.691T>C	p.Ser231Pro	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.691T>C	p.Ser231Pro	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.787T>C		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7	c.676T>C	p.Ser226Pro	missense_variant	Exon 7 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.*128T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:6

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 231 of the PAH protein (p.Ser231Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18346471, 27682710). ClinVar contains an entry for this variant (Variation ID: 102786). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8535444, 10394930). For these reasons, this variant has been classified as Pathogenic. -

Mar 08, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.691T>C (p.Ser231Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251314 control chromosomes. c.691T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser231Pro variant has been reported at least seven individuals with phenylketonuria (PKU) in the homozygous or compound heterozygous state (Effat 1999, Daniele 2008, Hamzelhoei 2012, Ajami 2013), and was not identified in large population studies. In vitro functional assays suggest complete loss of enzymatic activity (Dianzani 1995). In summary, this variant meets our criteria to be classified as pathogenic for PKU in an autosomal recessive manner for PKU based upon presence in affected individuals, absence from controls, and functional evidence (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/). -

not provided Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.5	H;.
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.94		Gain of catalytic residue at S231 (P = 0.0248);.;
MVP		1.0
MPC		0.26
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5030845; hg19: chr12-103248929;