ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2934C>G (p.Asp978Glu) (rs138438849)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181399 SCV000233701 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing The D978E variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes project report D978E was observed in 23/4396 alleles and 6/1322 alleles (0.5%) from individuals of African American background, indicating it may be a rare benign variant in this population. Although the D978E variant occurs at a position that is conserved across species, this substitution is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Consequently, in silico analysis is inconsistent in its predictions as to whether or not this variant is damaging to the protein structure/function. Furthermore, this variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000248615 SCV000317791 uncertain significance Cardiovascular phenotype 2017-05-12 criteria provided, single submitter clinical testing The p.D978E variant (also known as c.2934C>G), located in coding exon 24 of the FBN1 gene, results from a C to G substitution at nucleotide position 2934. The aspartic acid at codon 978 is replaced by glutamic acid, an amino acid with highly similar properties, and is located in the TGFBP #03 domain. Based on data from gnomAD, the G allele has an overall frequency of approximately 0.04% (99/277188) total alleles studied. The highest observed frequency was 0.39% (94/24020) of African 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.
Invitae RCV001088772 SCV000753166 benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-11-26 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659521 SCV000781347 uncertain significance Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757268 SCV000885423 likely benign none provided 2019-11-16 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767970 SCV000898697 uncertain significance Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-10-24 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 25 p.Asp978Glu (c.2934C>G): This variant has not been reported in the literature but is present in 0.4% (94/24020) of African alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs138438849). This variant is present in ClinVar (Variation ID:199947). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Health, Inc RCV001183737 SCV001349551 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-01-08 criteria provided, single submitter clinical testing

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