12-102843695-G-A

Variant names:

• chr12-102843695-G-A
• rs1555203677
• NM_000277.3:c.1150C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PM2

This summary comes from the ClinGen Evidence Repository: The c.1150C>T (p.Pro384Ser) PAH variant has been reported in at least one “phenylketonuria” or “hyperphenylalaninemia” proband (PMID:31332730). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020950/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 8.04
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.1150C>T	p.Pro384Ser	missense_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1150C>T	p.Pro384Ser	missense_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1150C>T	p.Pro384Ser	missense_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461392 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111618

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:3

Mar 28, 2017

Counsyl

Significance: Uncertain significance

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. -

Apr 23, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1150C>T (p.Pro384Ser) PAH variant has been reported in at least one “phenylketonuria” or “hyperphenylalaninemia” proband (PMID: 31332730). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. -

Jun 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 384 of the PAH protein (p.Pro384Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 26803807, 32668217). ClinVar contains an entry for this variant (Variation ID: 551270). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 26803807). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Oct 25, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.1150C>T (p.Pro384Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1150C>T in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) has been reported although it has been cited as being a mild variant in the literature (example, Shen_2016, Trunzo_2016, Zhang_2016) and has also been subsequently cited by others without primary evidence supporting pathogenicity (example, Kuznetcova_2019, Hillert_2020). Multiple overlapping publications report experimental evidence evaluating an impact on protein function (example, Shen_2016, Trunzo_2016, Zhang_2016). The most pronounced variant effect results in >50%-90% of normal phenylalanine hydroxylase enzyme activity in-vitro and positive interallelic complementation when analyzed as a compound heterozygous genotype with p.R408W. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.90
Sift	Benign	0.14	T;T
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.70		Loss of sheet (P = 0.0817);.;
MVP		1.0
MPC		0.24
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.92
Mutation Taster		=4/96	disease causing

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: rs1555203677; hg19: chr12-103237473;