Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Centre for Mendelian Genomics, |
RCV000415125 | SCV000492768 | pathogenic | Short stature; Conductive hearing impairment; Cleft palate | 2015-10-21 | criteria provided, single submitter | clinical testing | |
| Institute Of Human Genetics Munich, |
RCV000012521 | SCV001150103 | pathogenic | Oto-palato-digital syndrome, type I | 2020-01-16 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001000894 | SCV001157976 | pathogenic | not specified | 2018-11-20 | criteria provided, single submitter | clinical testing | The FLNA c.620C>T; p.Pro207Leu variant (rs28935469) has been described in individuals with otopalatodigital (OPD) syndrome type I (OPD1), and has shown to segregate with disease in males in at least 2 families (Robertson 2003). It contains an entry in ClinVar (Variation ID: 11755) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 207 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. This variant is located in a calponin homology domain portion of the actin-binding domain, and several variants within this region are associated with OPD syndrome type I and type II, indicating that this domain is likely important for protein function (Hidalgo-Bravo 2005, Kondoh 2007, Marino-Enriquez 2007, Robertson 2003, Sankararaman 2013). Based on available information, this variant is considered pathogenic. REFERENCES Hidalgo-Bravo A et al. A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation. Am J Med Genet A. 2005 Jul 15;136(2):190-3. Kondoh T et al. A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype-genotype correlation. J Hum Genet. 2007;52(4):370-3. Marino-Enriquez A et al. Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G>T mutation: clinical, pathological, and molecular findings. Am J Med Genet A. 2007 May 15;143A(10):1120-5. Robertson S et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. Sankararaman S et al. Otopalatodigital syndrome type 2 in a male infant: A case report with a novel sequence variation. J Pediatr Genet. 2013 Mar;2(1):33-6. |
| DASA | RCV001813739 | SCV002061276 | pathogenic | FLNA related disorders | 2022-01-05 | criteria provided, single submitter | clinical testing | The c.620C>T;p.(Pro207Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11755; OMIM: 300017.0009; PMID: 12612583; 31942422; 16538226) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (CH domain; PMID: 15917206) - PM1. This variant is not present in population databases (rs28935469, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 12612583; 31942422; 16538226) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. |
| Ambry Genetics | RCV002354156 | SCV002655076 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-01-24 | criteria provided, single submitter | clinical testing | The p.P207L variant (also known as c.620C>T), located in coding exon 2 of the FLNA gene, results from a C to T substitution at nucleotide position 620. The proline at codon 207 is replaced by leucine, an amino acid with similar properties. This alteration was first reported to segregate with type I otopalatodigital syndrome (OPD1) in two presumably unrelated families (Dudding BA et al. Am. J. Dis. Child., 1967 Feb;113:214-21; Robertson SP et al. Nat. Genet., 2003 Apr;33:487-91). This alteration was later reported in two affected brothers in a third family with OPD1, where it was not detected in the leukocyte DNA obtained from the mother. Two unaffected brothers in this family were not available for testing (Robertson SP et al. Eur. J. Hum. Genet., 2006 May;14:549-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV002509151 | SCV002818816 | pathogenic | not provided | 2022-12-16 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12612583, 6019437, 34277511, 31942422, 16538226) |
| Invitae | RCV003764562 | SCV004571552 | pathogenic | Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia | 2022-12-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 11755). This missense change has been observed in individuals with otopalatodigital syndrome (PMID: 3265608, 6019437, 12612583, 16538226, 31942422). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 207 of the FLNA protein (p.Pro207Leu). |
| OMIM | RCV000012521 | SCV000032755 | pathogenic | Oto-palato-digital syndrome, type I | 2003-04-01 | no assertion criteria provided | literature only |