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

gnomAD frequency: 0.00001  dbSNP: rs199475618

Total submissions: 7

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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Invitae	RCV000587503	SCV002173164	pathogenic	Phenylketonuria	2024-01-25	criteria provided, single submitter	clinical testing	This variant, c.967_969del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Thr323del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199475618, gnomAD 0.02%). This variant has been observed in individual(s) with phenylketonuria (PMID: 18299955, 21871829, 30829006). ClinVar contains an entry for this variant (Variation ID: 102913). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 18590700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000587503	SCV004209588	pathogenic	Phenylketonuria	2023-09-13	criteria provided, single submitter	clinical testing
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
Natera, Inc.	RCV000587503	SCV001463126	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing