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_000277.3(PAH):c.975C>G (p.Tyr325Ter)

CA229885

102921 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ffc9ce25-3e96-452a-a50d-a684e04b5bff

HGVS expressions

NM_000277.3:c.975C>G

NM_000277.3(PAH):c.975C>G (p.Tyr325Ter)

NC_000012.12:g.102844426G>C

CM000674.2:g.102844426G>C

NC_000012.11:g.103238204G>C

CM000674.1:g.103238204G>C

NC_000012.10:g.101762334G>C

NG_008690.1:g.78177C>G

NG_008690.2:g.118985C>G

NM_000277.1:c.975C>G

NM_000277.2:c.975C>G

NM_001354304.1:c.975C>G

NM_001354304.2:c.975C>G

ENST00000307000.7:c.960C>G

ENST00000549247.6:n.734C>G

ENST00000551114.2:n.637C>G

ENST00000553106.5:c.975C>G

ENST00000635477.1:n.79C>G

ENST00000635528.1:n.490C>G

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM2 PP4_Moderate PM3_Very Strong

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.975C>G (p.Tyr325Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least 13 PKU probands, at least 5 of whom BH4 deficiency was formally excluded (PP4_Moderate), including in trans with pathogenic or likely pathogenic variants in 9 cases, in trans with VUS in two cases, and homozygous in two cases (PM3_VeryStrong). It was first identified in a Korean patient with classic PKU (as confirmed by blood Phe levels) in trans with the N207D variant (pathogenic per PAH VCEP) (PMID: 9452061; PMID: 15503242); BH4 deficiency was excluded by urinary pterin analysis and DPHR assay. It was also found in another four patients with PKU, BH4 deficiency was excluded by urinary pterin analysis and DPHR assay (PMID: 15503242): one in trans with the known pathogenic (per PAH VCEP and in Clinvar) p.R413P variant (patient’s PKU phenotype not specified); one with classic PKU in trans with the known pathogenic (per PAH VCEP) p.V388M variant; one with mild hyperphenylalanemia in trans with the ClinVar pathogenic p.Y204C variant; and one in trans with the known pathogenic (per PAH VCEP) p. R243Q variant (PKU phenotype not specified). It has also been found in a Hispanic patient with classic PKU and BH4 deficiency excluded in trans with the pathogenic (per PAH VCEP) p.R261X variant (PMID: 23430918). It has also been found in 9 Chinese PKU cases (PMID: 26503515; PMID: 30050108), BH4 deficiency does not appear to have been ruled out: 2 homozygotes (classic PKU); one classic PKU case in trans with p.EX6-96A>G variant (pathogenic per PAH VCEP); one classic PKU case in trans with c.843-14_-11delCTTT (no PAH VCEP classification); one mild PKU case in trans with p.A434D (pathogenic per PAH VCEP); one mild hyperphenylalanemia case in trans with p.R241C (ClinVar pathogenic, PAH VCEP pathogenic); one classic PKU case in trans with p.Y206C (Likely pathogenic per PAH VCEP); and one mild hyperphenylalanemia case in trans with p.T418P (VUS per PAH VCEP). It is also listed Pathogenic in ClinVar by two labs (variant ID 102921). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate

PVS1

nonsense p.Tyr325Ter

PM2

GnomAD 4.07e-6

PP4_Moderate

It has been identified in at least 13 PKU probands, at least 5 of whom BH4 deficiency was formally excluded (PP4_Moderate), including in trans with pathogenic or likely pathogenic variants in 9 cases, in trans with VUS in two cases, and homozygous in two cases (PM3_VeryStrong). It was first identified in a Korean patient with classic PKU (as confirmed by blood Phe levels) in trans with the N207D variant (pathogenic per PAH VCEP) (PMID: 9452061; PMID: 15503242); BH4 deficiency was excluded by urinary pterin analysis and DPHR assay. It was also found in another four patients with PKU, BH4 deficiency was excluded by urinary pterin analysis and DPHR assay (PMID: 15503242): one in trans with the known pathogenic (per PAH VCEP and in Clinvar) p.R413P variant (patient’s PKU phenotype not specified); one with classic PKU in trans with the known pathogenic (per PAH VCEP) p.V388M variant; one with mild hyperphenylalanemia in trans with the ClinVar pathogenic p.Y204C variant; and one in trans with the known pathogenic (per PAH VCEP) p. R243Q variant (PKU phenotype not specified). It has also been found in a Hispanic patient with classic PKU and BH4 deficiency excluded in trans with the pathogenic (per PAH VCEP) p.R261X variant (PMID: 23430918). It has also been found in 9 Chinese PKU cases (PMID: 26503515; PMID: 30050108), BH4 deficiency does not appear to have been ruled out: 2 homozygotes (classic PKU); one classic PKU case in trans with p.EX6-96A>G variant (pathogenic per PAH VCEP); one classic PKU case in trans with c.843-14_-11delCTTT (no PAH VCEP classification); one mild PKU case in trans with p.A434D (pathogenic per PAH VCEP); one mild hyperphenylalanemia case in trans with p.R241C (ClinVar pathogenic, PAH VCEP pathogenic); one classic PKU case in trans with p.Y206C (Likely pathogenic per PAH VCEP); and one mild hyperphenylalanemia case in trans with p.T418P (VUS per PAH VCEP). It is also listed Pathogenic in ClinVar by two labs (variant ID 102921).

BH4 defect excluded PubMed:18985011

PM3_Very Strong

two patients with this variant, both patients in trans with a second pathogenic variant. PubMed:18985011

Approved on: 2020-04-13

Published on: 2020-04-13

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