Submissions for variant NM_000277.3(PAH):c.208_210del (p.Ser70del)

dbSNP: rs62642094

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411181	SCV000852172	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. 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: (PP4, PM3, PS3, PM2, PM4).
Counsyl	RCV000411181	SCV000485378	pathogenic	Phenylketonuria	2015-11-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411181	SCV000629188	pathogenic	Phenylketonuria	2024-11-19	criteria provided, single submitter	clinical testing	This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; internal data). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411181	SCV002015201	pathogenic	Phenylketonuria	2021-10-07	criteria provided, single submitter	clinical testing	Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000411181	SCV002016477	pathogenic	Phenylketonuria	2021-07-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411181	SCV004209585	pathogenic	Phenylketonuria	2023-11-17	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000411181	SCV005416948	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM4+PM3_VeryStrong
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088875	SCV000119469	not provided	not provided		flagged submission	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088875	SCV000119470	not provided	not provided		flagged submission	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088875	SCV000119472	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000411181	SCV001455114	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing