ClinVar Miner

Submissions for variant NM_000130.5(F5):c.6401C>T (p.Thr2134Met)

gnomAD frequency: 0.00016  dbSNP: rs199601865
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320829 SCV004025193 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003761199 SCV004508505 uncertain significance Congenital factor V deficiency 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2134 of the F5 protein (p.Thr2134Met). This variant is present in population databases (rs199601865, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with F5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049414). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355501 SCV001550407 uncertain significance not provided no assertion criteria provided clinical testing The F5 p.Thr2134Met variant was not identified in ClinVar but was identified in dbSNP (ID: rs199601865), Cosmic (FATHMM pathogenic prediction, score=0.89) and LOVD 3.0. The variant was identified in control databases in 61 of 282186 chromosomes at a frequency of 0.000216 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 10358 chromosomes (freq: 0.001062), European (Finnish) in 13 of 25020 chromosomes (freq: 0.00052), Other in 3 of 7210 chromosomes (freq: 0.000416), European (non-Finnish) in 33 of 128742 chromosomes (freq: 0.000256) and South Asian in 1 of 30612 chromosomes (freq: 0.000033); it was not observed in the African, Latino, and East Asian populations. The p.T2134M variant was identified in 1/26 patients (freq=0.019) with thrombotic storm (Nuytemans_2018_PMID: 29178990). The p.Thr2134 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, 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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