Submissions for variant NM_000286.3(PEX12):c.888_889del (p.Leu297fs)

dbSNP: rs398123301

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078563	SCV000110419	pathogenic	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078563	SCV000510758	pathogenic	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586945	SCV000696482	pathogenic	Peroxisome biogenesis disorder	2016-07-21	criteria provided, single submitter	clinical testing	Variant summary: The PEX12 c.888_889delCT (p.Leu297Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX12 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121406 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX12 variant (0.0015811). The variant has been identified in multiple affected individuals in heterozygous and homozygous state. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000412263	SCV001194154	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2020-01-06	criteria provided, single submitter	clinical testing	NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, 14571262, 15542397 and 21031596. Classification of NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Myriad Genetics, Inc.	RCV000410739	SCV001194155	pathogenic	Peroxisome biogenesis disorder type 3B	2020-01-06	criteria provided, single submitter	clinical testing	NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, 14571262, 15542397 and 21031596. Classification of NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412263	SCV001234961	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu297Thrfs*12) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs398123301, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with PEX12-related conditions (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). ClinVar contains an entry for this variant (Variation ID: 92776). 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.
Revvity Omics, Revvity	RCV000078563	SCV002016584	pathogenic	not provided	2020-03-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000078563	SCV002526175	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 63 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.887_888delTC using alternate nomenclature; This variant is associated with the following publications: (PMID: 31395954, 9792857, 34426522, 31589614, 21031596, 32005694, 34440436, 15542397, 29619570, 14571262, 32483926, 26094004)
Fulgent Genetics, Fulgent Genetics	RCV002477223	SCV002786956	pathogenic	Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger)	2022-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514382	SCV003699409	pathogenic	Inborn genetic diseases	2021-09-22	criteria provided, single submitter	clinical testing	The c.888_889delCT (p.L297Tfs*12) alteration, located in exon 3 (coding exon 3) of the PEX12 gene, consists of a deletion of 2 nucleotides from position 888 to 889, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration occurs at the 3' terminus of the PEX12 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 17% of the protein. Premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in multiple individuals with PEX12-related peroxisome biogenesis disorder, in the homozygous state, the compound heterozygous state, and in the heterozygous state without a second alteration identified (Chang, 1998; Ebberink, 2011; Gootjes, 2004; Konkoová, 2015; Salpietro, 2015; Steinberg, 2004; Wojcik, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000412263	SCV004201434	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000412263	SCV000494456	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	1998-11-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004739344	SCV005360401	pathogenic	PEX12-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The PEX12 c.888_889delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu297Thrfs*12). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Zellweger syndrome (Chang and Gould 1998. PubMed ID: 9792857; Gootjes et al. 2004. PubMed ID: 14571262; Ebberink et al. 2011. PubMed ID: 21031596; Salpietro et al. 2015. PubMed ID: 25287621). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. Frameshift variants in PEX12 are expected to be pathogenic. This variant is interpreted as pathogenic.