ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.637C>T (p.Leu213Phe) (rs141798874)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000306324 SCV000337835 likely benign not specified 2015-12-09 criteria provided, single submitter clinical testing
Invitae RCV001420972 SCV001033376 likely benign Zellweger syndrome 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.

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