ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.65C>A (p.Thr22Lys)

gnomAD frequency: 0.00013  dbSNP: rs199565868
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664768 SCV000788778 uncertain significance Phenylketonuria 2017-01-05 criteria provided, single submitter clinical testing
Invitae RCV000664768 SCV002131443 uncertain significance Phenylketonuria 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 22 of the PAH protein (p.Thr22Lys). This variant is present in population databases (rs199565868, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 550122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265840 SCV002547956 uncertain significance not specified 2022-05-18 criteria provided, single submitter clinical testing Variant summary: PAH c.65C>A (p.Thr22Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251346 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (8.8e-05 vs 0.0079), allowing no conclusion about variant significance. c.65C>A has been reported in the literature in individuals affected with melanoma (Arbesman_2018). The report does not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV000664768 SCV002782437 uncertain significance Phenylketonuria 2021-08-06 criteria provided, single submitter clinical testing

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