ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.113_115TCT[1] (p.Phe39del) (rs199475565)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169302 SCV000220621 likely pathogenic Phenylketonuria 2014-08-22 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000186077 SCV000227084 pathogenic not provided 2014-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000186077 SCV000239099 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The c.116_118delTCT variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium Database. The c.116_118delTCT has previously been reported in association with both mild PKU and hyperphenylalaninemia (Gjetting et al., 2001; Couce et al., 2013). The c.116_118delTCT variant results in the loss of a single phenylalanine codon at amino acid position 39, denoted p.Phe39del. Functional analysis of c.116_118delTCT found that it is associated with approximately 20% residual enzyme activity (Gjetting et al., 2001; Zurfluh et al, 2008). BH4 responsiveness is inconsistent in patients with c.116_118delTCT (Zurfluh et al, 2008; Sarkissian et al.,2012; Couce et al., 2013).
Integrated Genetics/Laboratory Corporation of America RCV000169302 SCV000917931 pathogenic Phenylketonuria 2018-11-23 criteria provided, single submitter clinical testing Variant summary: PAH c.116_118delTCT (p.Phe39del) results in an in-frame deletion that is predicted to remove a Phe amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 246172 control chromosomes. c.116_118delTCT has been reported in the literature in multiple individuals affected with classic and mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and mild hyperphenylalaninemia (Aldamiz-Echevarria_2016 and Zurfluh_2008). The variant was indicated to have 20% PAH enzyme activity (Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169302 SCV000932924 pathogenic Phenylketonuria 2018-11-26 criteria provided, single submitter clinical testing This variant, c.116_118delTCT, results in the deletion of 1 amino acid of the PAH protein (p.Phe39del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762462102, ExAC 0.004%). This variant has been observed to be homozygous or in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 9452062, 16256386, 19394257, 23500595, 26210745, 26542770, 12655550). This variant is also known as DF39 in the literature.ClinVar contains an entry for this variant (Variation ID: 188933). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. Variants that disrupt the p.Phe39 amino acid residue in PAH have been observed in affected individuals (PMID: 8592329, 8659548, 12655544, 12655553, 17935162, 206386). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000186077 SCV001250402 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000186077 SCV000119358 not provided not provided no assertion provided not provided

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