ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.3992C>T (p.Pro1331Leu) (rs149348098)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765162 SCV000896391 uncertain significance SPERMATOGENIC FAILURE 28; PREMATURE OVARIAN FAILURE 15 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000522616 SCV000621084 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing The P1331L variant in the FANCM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 12/66,390 alleles (0.18%) from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The P1331L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species. We interpret P1331L as a variant of uncertain significance.
Invitae RCV000630947 SCV000751922 uncertain significance Fanconi anemia 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1331 of the FANCM protein (p.Pro1331Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs149348098, ExAC 0.02%). This variant has not been reported in the literature in individuals with FANCM-related disease. ClinVar contains an entry for this variant (Variation ID: 452291). 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. 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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