ClinVar Miner

Submissions for variant NM_000128.3(F11):c.1716+1G>A (rs373297713)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012665 SCV000677913 pathogenic Hereditary factor XI deficiency disease 2015-10-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000012665 SCV000916058 pathogenic Hereditary factor XI deficiency disease 2018-10-31 criteria provided, single submitter clinical testing The F11 c.1716+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1716+1G>A variant has been described as a founder mutation in the Ashkenazi Jewish population (Peretz et al. 2013). The c.1716+1G>A variant has been reported in three studies and was found in a total of 30 probands from 14 families of Ashkenazi Jewish descent and one family of unknown ethnicity with factor XI deficiency, including in one in a homozygous state, in 12 in a compound heterozygous state, and in 17 in a heterozygous state (Asakai et al. 1989, Mitchell et al. 2006, Peretz et al. 2013). The c.1716+1G>A variant was shown to segregate with the disease in two studies and was absent from 491 healthy Ashkenazi Jewish controls (Asakai et al. 1989, Peretz et al. 2013). The variant is reported at a frequency of 0.000406 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, the c.1716+1G>A variant is classified as pathogenic for Factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001383739 SCV001582993 pathogenic not provided 2020-01-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 14) of the F11 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs373297713, ExAC 0.004%). This variant has been observed in individual(s) with Factor XI deficiency (PMID: 23332144, 2813350, 16835901). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11890). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts a region of the protein in which other variant(s) (p.Thr593Met) have been observed in individuals with F11-related conditions (PMID: 15749683, 27067486). This suggests that this may be a clinically significant region of the F11 protein. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012665 SCV000032900 pathogenic Hereditary factor XI deficiency disease 1989-10-01 no assertion criteria provided literature only

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