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  • See Evidence submitted by expert panel for details.

Variant: NM_000277.3(PAH):c.822_832del (p.Lys274fs)

CA229788

102852 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 9792fda2-ee97-4970-88ff-83689c4e9689

HGVS expressions

NM_000277.3:c.822_832del
NM_000277.3(PAH):c.822_832del (p.Lys274fs)
NC_000012.12:g.102852826_102852836del
CM000674.2:g.102852826_102852836del
NC_000012.11:g.103246604_103246614del
CM000674.1:g.103246604_103246614del
NC_000012.10:g.101770734_101770744del
NG_008690.1:g.69768_69778del
NG_008690.2:g.110576_110586del
NM_000277.1:c.822_832del
NM_000277.2:c.822_832del
NM_001354304.1:c.822_832del
NM_001354304.2:c.822_832del
ENST00000307000.7:c.807_817del
ENST00000549247.6:n.581_591del
ENST00000553106.5:c.822_832del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PP4_Moderate PVS1 PM2 PM3_Very Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.822_832delGCCCATGTATA (p.Lys274Asnfs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It has been previously reported in Clinvar (variation ID 102852) without any classification. It has been previously reported in at least 7 cases with PKU (confirmed by abnormal blood Phe levels) in whom BH4 deficiency was excluded (PP4_Moderate); it has also been noted in one case with hyperphenyalanemia. As detailed below, it has been found in confirmed trans with multiple known pathogenic variants (e.g., p.R408W, p.R261Q, p.F39del, p.A104D) in six probands total and in trans with a VUS (p.T81P variant) in one case (PM3_VeryStrong). These reports are as follows. It has been previously found in two unrelated German probands with classic PKU (determined by blood Phe levels); BH4 deficiency does not appear to have been formally excluded (PMID: 1363786). The two unrelated patients in this report (PMID: 1363786) were each confirmed compound heterozygotes: one carried it in trans with the known pathogenic p.R408W allele and the other carried it in trans with the known pathogenic p.R261Q allele (these two variants have been classified pathogenic per PAH VCEP). It has also been identified in two unrelated European PKU cases in whom BH4 deficiency was said to be excluded, each of whom were confirmed compound heterozygous for the variant with the known pathogenic p.R408Q allele (PMID: 24190797). In another report, it was found in confirmed trans in three white European cases in whom BH4 deficiency was said to be excluded and who presented with classic PKU by blood Phe levels: one case with the c.115_117delTTC (p.F39del) variant (Pathogenic per PAH VCEP), one case with the p.T81P variant (VUS per PAH VCEP), and one case with the p.A104D variant (Pathogenic per PAH VCEP) (PMID: 23430918). It has also been noted in a cohort of Czech patients with hyperphenylalanemia, but further detail does not appear to be provided (PMID: 23357515). Classification: Pathogenic Supporting criteria: PVS1, PM2, PM3_VeryStrong, PP4_Moderate
Met criteria codes
PP4_Moderate
It has been previously reported in at least 7 cases with PKU (confirmed by abnormal blood Phe levels) in whom BH4 deficiency was excluded (PP4_Moderate); it has also been noted in one case with hyperphenyalanemia. As detailed below, it has been found in confirmed trans with multiple known pathogenic variants (e.g., p.R408W, p.R261Q, p.F39del, p.A104D) in six probands total and in trans with a VUS (p.T81P variant) in one case (PM3_VeryStrong). These reports are as follows. It has been previously found in two unrelated German probands with classic PKU (determined by blood Phe levels); BH4 deficiency does not appear to have been formally excluded (PMID: 1363786). The two unrelated patients in this report (PMID: 1363786) were each confirmed compound heterozygotes: one carried it in trans with the known pathogenic p.R408W allele and the other carried it in trans with the known pathogenic p.R261Q allele (these two variants have been classified pathogenic per PAH VCEP). It has also been identified in two unrelated European PKU cases in whom BH4 deficiency was said to be excluded, each of whom were confirmed compound heterozygous for the variant with the known pathogenic p.R408Q allele (PMID: 24190797). In another report, it was found in confirmed trans in three white European cases in whom BH4 deficiency was said to be excluded and who presented with classic PKU by blood Phe levels: one case with the c.115_117delTTC (p.F39del) variant (Pathogenic per PAH VCEP), one case with the p.T81P variant (VUS per PAH VCEP), and one case with the p.A104D variant (Pathogenic per PAH VCEP) (PMID: 23430918). It has also been noted in a cohort of Czech patients with hyperphenylalanemia, but further detail does not appear to be provided (PMID: 23357515).
PVS1
The c.822_832delGCCCATGTATA (p.Lys274Asnfs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1).
PM2
It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2).
PM3_Very Strong
It has been previously reported in at least 7 cases with PKU (confirmed by abnormal blood Phe levels) in whom BH4 deficiency was excluded (PP4_Moderate); it has also been noted in one case with hyperphenyalanemia. As detailed below, it has been found in confirmed trans with multiple known pathogenic variants (e.g., p.R408W, p.R261Q, p.F39del, p.A104D) in six probands total and in trans with a VUS (p.T81P variant) in one case (PM3_VeryStrong). These reports are as follows. It has been previously found in two unrelated German probands with classic PKU (determined by blood Phe levels); BH4 deficiency does not appear to have been formally excluded (PMID: 1363786). The two unrelated patients in this report (PMID: 1363786) were each confirmed compound heterozygotes: one carried it in trans with the known pathogenic p.R408W allele and the other carried it in trans with the known pathogenic p.R261Q allele (these two variants have been classified pathogenic per PAH VCEP). It has also been identified in two unrelated European PKU cases in whom BH4 deficiency was said to be excluded, each of whom were confirmed compound heterozygous for the variant with the known pathogenic p.R408Q allele (PMID: 24190797). In another report, it was found in confirmed trans in three white European cases in whom BH4 deficiency was said to be excluded and who presented with classic PKU by blood Phe levels: one case with the c.115_117delTTC (p.F39del) variant (Pathogenic per PAH VCEP), one case with the p.T81P variant (VUS per PAH VCEP), and one case with the p.A104D variant (Pathogenic per PAH VCEP) (PMID: 23430918). It has also been noted in a cohort of Czech patients with hyperphenylalanemia, but further detail does not appear to be provided (PMID: 23357515).
Approved on: 2020-04-05
Published on: 2020-04-06
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