Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000277.1(PAH):c.935G>A (p.Gly312Asp)

CA229857

102901 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: d7f480cd-9e8f-47a8-b380-d7698998cae2
Approved on: 2020-07-27
Published on: 2020-07-27

HGVS expressions

NM_000277.1:c.935G>A
NM_000277.1(PAH):c.935G>A (p.Gly312Asp)
NM_000277.2:c.935G>A
NM_001354304.1:c.935G>A
NM_000277.3:c.935G>A
NM_001354304.2:c.935G>A
ENST00000307000.7:c.920G>A
ENST00000549247.6:n.694G>A
ENST00000551114.2:n.597G>A
ENST00000553106.5:c.935G>A
ENST00000635477.1:n.74-2498G>A
ENST00000635528.1:n.450G>A
NC_000012.12:g.102846929C>T
CM000674.2:g.102846929C>T
NC_000012.11:g.103240707C>T
CM000674.1:g.103240707C>T
NC_000012.10:g.101764837C>T
NG_008690.1:g.75674G>A
NG_008690.2:g.116482G>A
More

Likely Pathogenic

Met criteria codes 4
PP4_Moderate PM3 PM2 PP3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The NM_000277.1(PAH):c.935G>A (p.Gly312Asp) variant is a missense variant in exon 9/13 of PAH. It has been reported in at least 3 PKU cases in presumed trans with other Pathogenic variants (PM3; 1.5 points total), in two of whom BH4 deficiency was excluded (PP4_Moderate). It has been previously reported in presumed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP) in two cases with mild PKU (plasma Phe 600–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has also been reported in presumed trans with the p. R408W variant (Pathogenic by ClinGen PAH VCEP) in a patient with classic PKU and with undefined BH4 responsiveness. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.958) (PP3). Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP4_Moderate; PP3
Met criteria codes
PP4_Moderate
It has been reported in at least 3 PKU cases in presumed trans with other Pathogenic variants (PM3; 1.5 points total), in two of whom BH4 deficiency was excluded (PP4_Moderate). It has been previously reported in presumed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP) in two cases with mild PKU (plasma Phe 60–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has also been reported in presumed trans with the p. R408W variant (Pathogenic by ClinGen PAH VCEP) in a patient with classic PKU and with undefined BH4 responsiveness.
Single patient reported G312D/R408W with undefined BH4 responsiveness and classic PKU PubMed:24350308
PM3
It has been reported in at least 3 PKU cases in presumed trans with other Pathogenic variants (PM3; 1.5 points total), in two of whom BH4 deficiency was excluded (PP4_Moderate). It has been previously reported in presumed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP) in two cases with mild PKU (plasma Phe 60–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has also been reported in presumed trans with the p. R408W variant (Pathogenic by ClinGen PAH VCEP) in a patient with classic PKU and with undefined BH4 responsiveness
Single patient reported G312D/R408W with undefined BH4 responsiveness and classic PKU PubMed:24350308
PM2
Not found in any pop database.
PP3
All computational evidence support a deleterious effect. REVEL=0.958
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.