rs62508734

Variant names:

• chr12-102852818-T-C
• rs62508734
• NM_000277.3:c.839A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-102852818-T-C
• chr12-102852818-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000277.3(PAH):​c.839A>G​(p.Glu280Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E280A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.02

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102852818-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 12-102852818-T-C is Pathogenic according to our data. Variant chr12-102852818-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 102866.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102852818-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.839A>G	p.Glu280Gly	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.839A>G	p.Glu280Gly	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.839A>G	p.Glu280Gly	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.824A>G	p.Glu275Gly	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.598A>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-2A>G		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phenylketonuria Pathogenic:1

Oct 12, 2017

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. This sequence change replaces glutamic acid with glycine at codon 280 of the PAH protein (p.Glu280Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with PKU (Invitae). In addition, this variant has been reported in combination with another PAH variant in an individual affected with PKU (PMID: 18247293). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 102866). Experimental studies have shown that this missense change impairs PAH enzyme activity in vitro (PMID: 18247293). A different missense substitution at this codon (p.Glu208Lys) has been determined to be pathogenic (PMID: 12655546, 17935162, 23500595, 2564729, 2014036, 12655546, 17935162, 21953985, 2014036, Invitae). This suggests that the glutamic acid residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. -

not provided Other:1

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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	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.8	H;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.98		Loss of catalytic residue at E280 (P = 0.0424);.;
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs62508734; hg19: chr12-103246596;