rs118203925

Variant names:

• chr12-102912819-G-A
• rs118203925
• NM_000277.3:c.140C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102912819-G-A
• chr12-102912819-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3_Strong PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID:24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114370/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 6.40
• Publications: 12 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.140C>T	p.Ala47Val	missense_variant	Exon 2 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.140C>T	p.Ala47Val	missense_variant	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2	c.140C>T	p.Ala47Val	missense_variant	Exon 2 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.140C>T	p.Ala47Val	missense_variant	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251412 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460924 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111242

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Aug 10, 2023

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.140C>T (p.Ala47Val) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.140C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and -mild hyperphenylalaninemia (examples: Aldamiz-Echevarria_2016, Bayat_2016, Ho_2013). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that this missense change affects PAH function (examples: Gjetting_MGM_2001, Gjetting_AJHG_2001, and Himmelreich_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11161839, 11326337, 30037505, 27121329, 24368688, and 26542770). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 22, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. -

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the PAH protein (p.Ala47Val). This variant is present in population databases (rs118203925, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 630). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 11326337, 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic. -

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperphenylalaninemia Pathogenic:1

May 15, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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	Benign	0.22
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;.;.
PhyloP100		6.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N;N;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.062	T;T;D;D
Sift4G	Benign	0.13	T;T;D;.
Polyphen		0.12	B;.;.;.
Vest4		0.91
MutPred		0.88		Gain of ubiquitination at K50 (P = 0.1111);.;Gain of ubiquitination at K50 (P = 0.1111);Gain of ubiquitination at K50 (P = 0.1111);
MVP		0.99
MPC		0.042
ClinPred		0.83	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.82
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118203925; hg19: chr12-103306597;