ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.968_970del (p.Thr323del) (rs199475618)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000587503 SCV000852121 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD: 0.000008131; PM4: Protein length change as a results of in-frame deletion; PP4_Moderate: T323del found in 2 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:21147011); PM3_Strong: T323del detected with P281 in 1 PKU patient, and L48S in another PKU patient. Both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:21147011). 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, PM4, PP4_Moderate, PM3_Strong).
Integrated Genetics/Laboratory Corporation of America RCV000587503 SCV000696474 pathogenic Phenylketonuria 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The PAH c.967_969delACA (p.Thr323del) variant is an in-frame deletion in non-repetitive region and is located in catalytic domain of the protein (Bercovich_2008). Although it leads to deletion of last 3 nucleotides in exon 9, 5/5 splice prediction tools predict no significant impact on normal splicing. However, mutation taster tool predicts a damaging outcome for this variant. This variant is absent in 121338 control chromosomes from ExAC. This variant has been reported in several PKU patients in homozygous as well as in compound heterozygous state with other pathogenic/likely pathogenic variants (Moller_2005, Bercovich_2008, Rivera_2011, Sarkissian_2012, Yano_2016). In vitro functional study indicates this variant leads to impairment of enzymatic function (Dobrowolski_2011). Taken together, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089178 SCV000119793 not provided not provided no assertion provided not provided
Counsyl RCV000587503 SCV000792038 likely pathogenic Phenylketonuria 2017-06-05 no assertion criteria provided clinical testing

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