Evidence Repository - Clinical Genome Resources

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

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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

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

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

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

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

PP3

All computational evidence support a deleterious effect. REVEL=0.958

PM3

Single patient reported G312D/R408W with undefined BH4 responsiveness and classic PKU PubMed:24350308

PM2

Not found in any pop database.

Approved on: 2020-07-27

Published on: 2020-07-27

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