ClinVar Miner

Submissions for variant NM_000128.3(F11):c.325G>A (p.Ala109Thr) (rs768474112)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169144 SCV000220364 likely pathogenic Hereditary factor XI deficiency disease 2014-05-31 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000169144 SCV001307529 uncertain significance Hereditary factor XI deficiency disease 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001380982 SCV001579225 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 109 of the F11 protein (p.Ala109Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 4 of the F11 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs768474112, ExAC 0.01%). This variant has been observed in individual(s) with factor XI (FXI) deficiency (PMID: 18515884, 25158988, 18446632, 18327400). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ala91Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 188810). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18327400). For these reasons, this variant has been classified as Pathogenic.

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