chr12-102844371-C-T

Variant names:

• chr12-102844371-C-T
• rs62508679
• NM_000277.3:c.1030G>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.1030G>A (p.Gly344Ser) variant in PAH has been reported in multiple individuals with PKU and mild PKU (BH4 deficiency excluded). (PMID:26503515, 29390883, 9634518). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Q419R (PMID:26600521). Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Arg, p.Gly344Val are Likely pathogenic by PAH VCEP). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229285/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 7.91

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 Likely_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.1030G>A	p.Gly344Ser	missense_variant	Exon 10 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1030G>A	p.Gly344Ser	missense_variant	Exon 11 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1030G>A	p.Gly344Ser	missense_variant	Exon 10 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Jun 11, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1030G>A (p.Gly344Ser) variant in PAH has been reported in multiple individuals with PKU and mild PKU (BH4 deficiency excluded). (PMID: 26503515, 29390883, 9634518). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Q419R (PMID: 26600521). Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Arg, p.Gly344Val are Likely pathogenic by PAH VCEP). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. -

Apr 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly344 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 10679941, 18985011), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with phenylketonuria (PMID: 26600521, 17502162). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102479). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 344 of the PAH protein (p.Gly344Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

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	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.9	H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Loss of sheet (P = 0.0817);.;
MVP		0.99
MPC		0.24
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs62508679; hg19: chr12-103238149; COSMIC: COSV61018368;