Submissions for variant NM_000466.3(PEX1):c.637C>T (p.Leu213Phe)

gnomAD frequency: 0.00185  dbSNP: rs141798874

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000306324	SCV000337835	likely benign	not specified	2015-12-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001420972	SCV001033376	likely benign	Zellweger spectrum disorders	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000889675	SCV001321003	uncertain significance	Peroxisome biogenesis disorder 1A (Zellweger)	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355075	SCV001549844	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PEX1 p.Leu5Phe variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs141798874), ClinVar (classified as ikely benign by EGL Genetic Diagnostics), and LOVD 3.0 (classified as benign by VKGL data sharing initiative Nederland) databases. The variant was identified in control databases in 156 of 223918 chromosomes (1 homozygous) at a frequency of 0.000697 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 147 of 24124 chromosomes (freq: 0.006094), Other in 4 of 5512 chromosomes (freq: 0.000726), Latino in 4 of 23394 chromosomes (freq: 0.000171), South Asian in 1 of 17134 chromosomes (freq: 0.000058), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The p.Leu5 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001355075	SCV001799080	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000306324	SCV001918790	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001355075	SCV001974664	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001420972	SCV002079340	likely benign	Zellweger spectrum disorders	2017-05-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003977775	SCV004799444	likely benign	PEX1-related disorder	2019-05-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).