ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)

dbSNP: rs387907371
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001091828 SCV001248061 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001205323 SCV001376572 pathogenic Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 2023-11-10 criteria provided, single submitter clinical testing This sequence change affects codon 1731 of the FLNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FLNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 16 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with terminal osseous dysplasia with pigmentary skin defects within the clinical scope of X-linked otopalatodigital spectrum disorders (PMID: 20598277, 26061098, 30561107, 31919883). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5217G>A. ClinVar contains an entry for this variant (Variation ID: 11775). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 30 (PMID: 20598277). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001292939 SCV001481646 pathogenic Heterotopia, periventricular, X-linked dominant 2020-01-07 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 20598277, 25614868, 26059211, 26061098, 30561107]
GeneDx RCV001091828 SCV005384165 pathogenic not provided 2024-04-25 criteria provided, single submitter clinical testing In silico analysis suggests this variant may impact gene splicing. In addition, RNA expression studies demonstrate that this variant activates a cryptic splice site, removing the last 16 amino acids in exon 31 (p.Val1724_Thr1739del) (PMID: 20598277); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26061098, 25614868, 31919883, 15864382, 10982965, 9800904, 26059211, 30561107, 20598277)
OMIM RCV000012542 SCV000032776 pathogenic Terminal osseous dysplasia-pigmentary defects syndrome 2010-07-09 no assertion criteria provided literature only
GeneReviews RCV000012542 SCV000086835 not provided Terminal osseous dysplasia-pigmentary defects syndrome no assertion provided literature only

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