12-102843675-CT-GC

Variant names:

• chr12-102843675-CT-GC
• NM_000277.3:c.1169_1170delAGinsGC
• PAH p.Glu390Gly

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2

The NM_000277.3(PAH):c.1169_1170delAGinsGC (p.Glu390Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E390= (synonymous): Likely_benign (ClinVar VariationId 1659442, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Phenylketonuria (pku).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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]

PAH Gene-Disease associations (from GenCC):

• classic phenylketonuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 10 pathogenic, 0 benign rare missense variants (OR vs. background: 105.0).; ±8 AA neighbourhood: 23 pathogenic, 0 benign (OR vs. background: 235.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH NM_000277.3	MANE Select	c.1169_1170delAGinsGC p.Glu390Gly	missense	N/A	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.1169_1170delAGinsGC p.Glu390Gly	missense	N/A	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.1169_1170delAGinsGCp.Glu390Gly

Exon rankN/A

missense

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.1169_1170delAGinsGCp.Glu390Gly

Exon rankN/A

missense

Prot: NP_001341233.1UniProt: P00439

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH ENST00000553106.6	TSL:1MANE Select	c.1169_1170delAGinsGC p.Glu390Gly	missense	N/A	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000906695.1		c.1268_1269delAGinsGC p.Glu423Gly	missense	N/A	Prot: ENSP00000576754.1 UniProt:
	PAH ENST00000906692.1		c.1247_1248delAGinsGC p.Glu416Gly	missense	N/A	Prot: ENSP00000576751.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.1169_1170delAGinsGCp.Glu390Gly

Exon rankN/A

missense

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000906695.1

HGVSc / HGVSpc.1268_1269delAGinsGCp.Glu423Gly

Exon rankN/A

missense

Prot: ENSP00000576754.1UniProt: A0ACI8RXH2

PAH ENST00000906692.1

HGVSc / HGVSpc.1247_1248delAGinsGCp.Glu416Gly

Exon rankN/A

missense

Prot: ENSP00000576751.1UniProt: A0ACI8S8A6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr12-103237453;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar