rs140175796

chr12-102877469-T-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):c.434A>T(p.Asp145Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,612,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D145E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 7.38

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr12-102877468-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1503089.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 12-102877469-T-A is Pathogenic according to our data. Variant chr12-102877469-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102667.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102877469-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.434A>T	p.Asp145Val	missense_variant	4/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.808-2410T>A		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.434A>T	p.Asp145Val	missense_variant	5/14
PAH	XM_017019370.2	c.434A>T	p.Asp145Val	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.434A>T	p.Asp145Val	missense_variant	4/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251484 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000849 AC: 124 AN: 1461042 Hom.: 0 Cov.: 31 AF XY: 0.0000880 AC XY: 64 AN XY: 726896

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000963

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151878 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74164

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:7

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 10, 2018	The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 21, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2023	Variant summary: PAH c.434A>T (p.Asp145Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.434A>T has been reported in the literature in several affected individuals with biochemically confirmed mild form of HPA or PKU, and was predicted to be BH4-responsive allele. The following publications have been ascertained in the context of this evaluation (PMID: 25087612, 24368688, 8659548, 26666653, 17096675, 27121329, 10541324). Eight 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The PAH c.434A>T (p.Asp145Val) missense variant has been reported in seven studies in which it is found in a total of seven individuals in a compound heterozygous state, and in one in a heterozygous state with no second variant detected (Guldberg et al. 1996, Mallolas et al. 1999, Yang et al. 2001, Aulehla-Scholz et al. 2003, Dahri et al. 2010, Ho et al. 2013, Jeannesson-Thivisol et al. 2015). Individuals with the p.Asp145Val variant were described as having mild hyperphenylalaninemia. The p.Asp145Val variant was absent from 620 healthy controls (Aulehla-Scholz et al. 2003, Ho et al. 2014) and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp145Val variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 145 of the PAH protein (p.Asp145Val). This variant is present in population databases (rs140175796, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylalanine levels >180 umol/L findings that are highly specific for hyperphenylalaninemia (PMID: 8659548, 26666653). ClinVar contains an entry for this variant (Variation ID: 102667). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 27121329). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26666653, 11180595, 24368688, 32778825, 10394930, 11678552, 10598814, 10527663, 31747680, 25087612, 27469133, 10429004, 17096675, 19786003, 11385716, 12655553, 14654663, 10541324, 31589614, 23514811, 27121329, 33465300, 32668217, 8659548) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 08, 2021	PP3, PP4_moderate, PM3_very_strong, PM5, PS3 -

PAH-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The PAH c.434A>T variant is predicted to result in the amino acid substitution p.Asp145Val. This variant has previously been reported, along with a second known pathogenic PAH variant, in patients with phenylalanine hydroxylase deficiency (for example, see Guldberg et al. 1996. PubMed ID: 8659548; Aulehla-Scholz and Heilbronner, 2003. PubMed ID: 12655553; Hillert et al. 2020. PubMed ID: 32668217). It has been reported that the p.Asp145Val amino acid substitution may result in a PAH protein that is somewhat responsive to tetrahydrobiopterin (BH4), although this has not been clearly established (Ho et al. 2014. PubMed ID: 24368688; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). Several other laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/102667/), and the ClinGen PAH Variant Curation Expert Panel classifies it as likely pathogenic (Zastrow et al. 2018. PubMed ID: 30311390). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103271247-T-A). In summary, the c.434A>T (p.Asp145Val) variant is interpreted as likely pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 09, 2020

ACMG classification criteria: PS4, PM2, PM3, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-8.4	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.98
MPC		0.27
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.91
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140175796; hg19: chr12-103271247;