rs199475578

Variant names:

• chr12-102852933-G-A
• rs199475578
• NM_000277.3:c.724C>T

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP4_Moderate PP3 PM3

This summary comes from the ClinGen Evidence Repository: The c.724C>T (p.Leu242Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID:1363786, 21147011). This variant is absent in population databases. It was detected with multiple pathogenic/likely pathogenic variants: p.R158Q (PMID:24190797); IVS10-11G>A (PMID:21147011); p.R252W (PMID:1363786); p.V399V (PMID:26600521); c.1315+4A>G (PMID:25456745); p.R408W (PMID:19244369); p.R241C (PMID:30050108); c.1068C>A p.Tyr356* (2 patients), p.Arg243Gln (PMID:28982351) 7.75 pts. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229718/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 3.31

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 7 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.
• PP3: 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.724C>T	p.Leu242Phe	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.724C>T	p.Leu242Phe	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.724C>T	p.Leu242Phe	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.709C>T	p.Leu237Phe	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.483C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-117C>T		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 32 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 Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

Nov 02, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.724C>T (p.Leu242Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 1363786, 21147011). This variant is absent in population databases. It was detected with multiple pathogenic/likely pathogenic variants: p.R158Q (PMID: 24190797); IVS10-11G>A (PMID: 21147011); p.R252W (PMID: 1363786); p.V399V (PMID: 26600521); c.1315+4A>G (PMID: 25456745); p.R408W (PMID: 19244369); p.R241C (PMID: 30050108); c.1068C>A p.Tyr356* (2 patients), p.Arg243Gln (PMID: 28982351) 7.75 pts. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. -

May 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 102807). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 1363786, 21147011, 25456745, 29390883). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 242 of the PAH protein (p.Leu242Phe). -

May 15, 2024

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.724C>T (p.Leu242Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of 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 251030 control chromosomes. c.724C>T has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)/Hyperphenylalaninemia (e.g. Cao_2014, Dworniczak_1992, Liu_2017, van Calcar_2009, Yan_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25456745, 1363786, 28982351, 32039316, 19244369). ClinVar contains an entry for this variant (Variation ID: 102807). Based on the evidence outlined above, the variant was classified as pathogenic. -

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	0.83
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0723);.;
MVP		0.95
MPC		0.24
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.94

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: rs199475578; hg19: chr12-103246711;