ClinVar Miner

Submissions for variant NM_000143.3(FH):c.132G>A (p.Met44Ile) (rs863223982)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561722 SCV000664725 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000807455 SCV000947508 uncertain significance Fumarase deficiency 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 44 of the FH protein (p.Met44Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 1 of the FH coding sequence, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 214393). 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). 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. 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.

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