ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.183C>A (p.Asn61Lys)

dbSNP: rs199475634
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000106350 SCV001592529 pathogenic Phenylketonuria 2023-08-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn61 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12501224; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 120269). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 10234516, 27121329). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 61 of the PAH protein (p.Asn61Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000106350 SCV004038790 likely pathogenic Phenylketonuria 2023-08-22 criteria provided, single submitter clinical testing Variant summary: PAH c.183C>A (p.Asn61Lys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250918 control chromosomes (gnomAD). To our knowledge, no occurrence of c.183C>A in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and no experimental evidence demonstrating its impact on protein function have been reported. A different variant resulting in the same amino acid change (c.183C>G, p.Asn61Lys -CV ID 102618) has been classified pathogenic in ClinVar. Additionally, other variants affecting the same codon (p.Asn61Ser, p.Asn61Asp) have been classified pathogenic/likely pathogenic in ClinVar (CV ID 1514901, 102617). This suggests this residue may be critical for normal protein function. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000106350 SCV004209568 pathogenic Phenylketonuria 2023-09-29 criteria provided, single submitter clinical testing
Inserm U 954, Faculté de Médecine de Nancy RCV000106350 SCV000143849 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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