ClinVar Miner

Submissions for variant NM_001171613.2(PREPL):c.818T>C (p.Phe273Ser)

gnomAD frequency: 0.00001  dbSNP: rs1347512792
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001871948 SCV002222066 uncertain significance Myasthenic syndrome, congenital, 22 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 362 of the PREPL protein (p.Phe362Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PREPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050574). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003169773 SCV003871047 uncertain significance Inborn genetic diseases 2023-02-13 criteria provided, single submitter clinical testing The c.1085T>C (p.F362S) alteration is located in exon 7 (coding exon 7) of the PREPL gene. This alteration results from a T to C substitution at nucleotide position 1085, causing the phenylalanine (F) at amino acid position 362 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358168 SCV001553839 uncertain significance not provided no assertion criteria provided clinical testing The PREPL p.Phe362Ser variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs1347512792) and in control databases in 6 of 250616 chromosomes at a frequency of 0.00002394 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 6 of 113368 chromosomes (freq: 0.000053), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Phe362 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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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