NM_000277.3:c.266_267insG

CA16020759

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 930a1a71-4d11-4274-a554-2dd6f23f3d63

Approved on: 2019-04-04

Published on: 2019-08-16

HGVS expressions

NM_000277.3:c.266_267insG
NC_000012.12:g.102894820_102894821insC
CM000674.2:g.102894820_102894821insC
NC_000012.11:g.103288598_103288599insC
CM000674.1:g.103288598_103288599insC
NC_000012.10:g.101812728_101812729insC
NG_008690.1:g.27782_27783insG
NG_008690.2:g.68590_68591insG
NM_000277.1:c.266_267insG
NM_000277.2:c.266_267insG
NM_001354304.1:c.266_267insG
ENST00000307000.7:c.251_252insG
ENST00000546844.1:c.266_267insG
ENST00000548677.2:n.353_354insG
ENST00000548928.1:n.188_189insG
ENST00000549111.5:n.362_363insG
ENST00000550978.6:n.250_251insG
ENST00000551337.5:c.266_267insG
ENST00000551988.5:n.355_356insG
ENST00000553106.5:c.266_267insG

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM3 PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916. The sequence change results in a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate.

Met criteria codes

• PVS1: The sequence change results in a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1).
• PP4_Moderate: The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916.
• PM3: The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916.
• PM2: It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).