ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1197A>T (p.Val399=) (rs199475584)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000632 SCV000852144 pathogenic Phenylketonuria 2018-07-28 reviewed by expert panel curation The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID: 23271928; PMID: 11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID: 11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID: 11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate
Integrated Genetics/Laboratory Corporation of America RCV000000632 SCV000696430 pathogenic Phenylketonuria 2016-08-05 criteria provided, single submitter clinical testing Variant summary: The PAH c.1197A>T (p.Val399Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. It is located three nucleotides upstream from exon-intron boundary and is predicted to be damaging by MutationTaster. In addition, 2/5 tools predict the variant to attenuate the splice donor site while 4/5 tools predict the variant to attenuate the cryptic splice site located at upstream to this variant position. Functional study by patients RNA analysis as well as minigene assay proves that this variant is a splicing mutation causing skipping of exon 11 (Chao_2001). This variant was found in 15/121712 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is a common pathogenic variant causing classical PKH, especially in Chinese and/or Taiwanese population with consistent clinical data. The carrier rate of this variant in Han Chinese population was 3.2% in a study that enrolled 212 controls (Zhu_2010). Multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088786 SCV000708636 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000632 SCV000814398 pathogenic Phenylketonuria 2019-10-08 criteria provided, single submitter clinical testing This sequence change affects codon 399 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with other PAH variants in individuals affected with PAH-related disease (PMID: 24401910, 27264808). This variant has also been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with PAH-related disease (PMID: 11214902, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 601). Experimental studies have shown that this silent change causes aberrant RNA splicing and exon skipping (PMID: 11214902). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000632 SCV000020782 pathogenic Phenylketonuria 2001-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088786 SCV000119373 not provided not provided no assertion provided not provided
Counsyl RCV000000632 SCV001132263 pathogenic Phenylketonuria 2015-03-19 no assertion criteria provided clinical testing

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