rs118203921

Positions:

• chr12-102852881-G-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.776C>T​(p.Ala259Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. A259T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 10.0

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 18 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr12-102852882-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 12-102852881-G-A is Pathogenic according to our data. Variant chr12-102852881-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102852881-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-102852881-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.776C>T	p.Ala259Val	missense_variant	7/13	ENST00000553106.6
PAH	NM_001354304.2	c.776C>T	p.Ala259Val	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.776C>T	p.Ala259Val	missense_variant	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.761C>T	p.Ala254Val	missense_variant	8/14	5
PAH	ENST00000549247.6	n.535C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251340 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135826

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 8304187, 9799096, 10479481). 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. ClinVar contains an entry for this variant (Variation ID: 602). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2035532, 18299955, 26666653). This variant is present in population databases (rs118203921, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the PAH protein (p.Ala259Val). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: PAH c.776C>T (p.Ala259Val) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 8e-06 in 251340 control chromosomes (gnomAD). c.776C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Koch_1997, Benit_1999, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <5% of normal activity (e.g. Benit_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10479481, 26666653, 9169088). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.99
MPC		0.23
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.97

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: rs118203921; hg19: chr12-103246659;