ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.3557C>T (p.Ser1186Leu) (rs137853312)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000012527 SCV000222836 pathogenic Frontometaphyseal dysplasia 1 2009-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000414151 SCV000490530 likely pathogenic not provided 2015-11-01 criteria provided, single submitter clinical testing The S1186L variant in the FLNA gene has been reported previously in at least three unrelated male probands with frontometaphyseal dysplasia (Robertson et al., 2003; Giuliano et al., 2005; Zenker et al., 2006). The mothers of two of the probands shared the features of prominent brow and hypertelorism, and were less severely affected than their sons, presumably due to skewed X-inactivation (Giuliano et al., 2005; Zenker et al., 2006). The S1186L variant is noted to segregate only with a FMD presentation in contrast to other FLNA variants where the same variant may present with different FLNA-related phenotypes (Zenker et al., 2006). The S1186L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1186L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D1184E, A1188T) have been reported in the Human Gene Mutation Database in association with Melnick-Needles syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The S1186L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000694493 SCV000822942 pathogenic Periventricular nodular heterotopia 1; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 1 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1186 of the FLNA protein (p.Ser1186Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with frontometaphyseal dysplasia (PMID: 16835913, 15523633, 16596676). In at least one of these individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 11761). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012527 SCV000032761 pathogenic Frontometaphyseal dysplasia 1 2006-05-15 no assertion criteria provided literature only

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