ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.1060C>T (p.His354Tyr)

gnomAD frequency: 0.00002  dbSNP: rs1489530369
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001345513 SCV001539636 uncertain significance Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 2020-07-15 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 354 of the FLNA protein (p.His354Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLNA-related conditions. 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: "Benign"; Align-GVGD: "Class C65"). 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.
Ambry Genetics RCV002412086 SCV002716103 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-05-18 criteria provided, single submitter clinical testing The p.H354Y variant (also known as c.1060C>T), located in coding exon 6 of the FLNA gene, results from a C to T substitution at nucleotide position 1060. The histidine at codon 354 is replaced by tyrosine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.005% (1/21932) total alleles studied, with no hemizygotes observed. The highest observed frequency was 0.01% (1/10738) of non-Finnish European alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002493774 SCV002779646 uncertain significance Cardiac valvular dysplasia, X-linked; FG syndrome 2; Heterotopia, periventricular, X-linked dominant; Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked; Melnick-Needles syndrome; Oto-palato-digital syndrome, type I; Oto-palato-digital syndrome, type II; Terminal osseous dysplasia-pigmentary defects syndrome; Frontometaphyseal dysplasia 1 2022-04-25 criteria provided, single submitter clinical testing
GeneDx RCV003159203 SCV003852955 uncertain significance not provided 2023-03-26 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; Has not been previously published as pathogenic or benign to our knowledge

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