ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.43_44CT[2] (p.Leu15_Ser16insTer) (rs62642906)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000153638 SCV000852108 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PM3, PP4).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088944 SCV000203188 pathogenic not provided 2014-04-02 criteria provided, single submitter clinical testing
Counsyl RCV000153638 SCV000221085 likely pathogenic Phenylketonuria 2015-01-26 criteria provided, single submitter literature only
Invitae RCV000153638 SCV000754077 pathogenic Phenylketonuria 2017-09-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser16*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62642906, ExAC 0.001%). This variant has been reported in several individuals affected with hyperphenylalaninemia and phenylketonuria (PMID: 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415). This variant is also known as c.44_45delTC, p.Ser16fs in the literature. ClinVar contains an entry for this variant (Variation ID: 102696). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000153638 SCV001362289 pathogenic Phenylketonuria 2019-03-25 criteria provided, single submitter clinical testing Variant summary: PAH c.47_48delCT (p.Ser16X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.165delT, p.Phe55fsX6; c.331C>T, p.Arg111X; c.556delA, p.Thr186fsX9). The variant allele was found at a frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Aldamiz-Echevarria_2016, Ramus_1995, Tao_2015, Trunzo_2015, Wang_2017). These data indicate that the variant is very likely to be associated with disease. In vitro expression experiment reports that PAH residual activity for this variant effect results in <10% of normal activity (Aldamiz-Echevarria_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088944 SCV000119545 not provided not provided no assertion provided not provided

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