ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.8282C>T (p.Ala2761Val)

gnomAD frequency: 0.00021  dbSNP: rs201962592
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000755536 SCV000250254 uncertain significance not provided 2023-03-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); 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: 18767143)
Illumina Laboratory Services, Illumina RCV000347766 SCV000452539 likely benign Congenital contractural arachnodactyly 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000347766 SCV000553168 likely benign Congenital contractural arachnodactyly 2024-01-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755536 SCV000603689 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing The p.Ala2761Val variant (rs201962592) has not been reported in the medical literature, gene specific variation databases, but it has been reported to ClinVar (see link below). This variant is listed in the Exome Aggregation Consortium Browser with a population frequency of 0.03 percent (identified on 20 out of 66,740 chromosomes) in non-Finnish European population. The alanine at position 2761 is highly conserved (up to Chicken, considering 11 species) (Alamut v.2.8.1) but Zebra-finch has valine at this position, and this non-cysteine residue is not located in the EGF-like domain. Computational analyses of the effects of the p.Ala2761Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Our laboratory has previously identified this variant in one individual with bifid uvula, submucous cleft, micrognathia, facial asymmetry, joint hypermobility, tracheomalacia, conductive hearing loss and developmental delay. Altogether, there is not enough evidence to classify the p.Ala2761Val variant with certainty.
Ambry Genetics RCV002315587 SCV000738992 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-04-13 criteria provided, single submitter clinical testing The p.A2761V variant (also known as c.8282C>T), located in coding exon 64 of the FBN2 gene, results from a C to T substitution at nucleotide position 8282. The alanine at codon 2761 is replaced by valine, an amino acid with similar properties, and is located in the fibulin-like domain. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000347766 SCV000781473 uncertain significance Congenital contractural arachnodactyly 2016-11-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000755536 SCV001501943 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252049 SCV002523881 uncertain significance See cases 2019-05-27 criteria provided, single submitter clinical testing ACMG classification criteria: PM2, BP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000347766 SCV002557259 uncertain significance Congenital contractural arachnodactyly 2020-06-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS–3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 64). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (55 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant previously been described as variant of uncertain significance (VUS). Six VUS entries in ClinVar. Previously observed in the VCGS cardiomyopathy cohort. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002277531 SCV002566602 uncertain significance Connective tissue disorder 2019-12-01 criteria provided, single submitter clinical testing

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