ClinVar Miner

Submissions for variant NM_006329.3(FBLN5):c.604G>A (p.Gly202Arg) (rs80338765)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427840 SCV000516149 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing The G202R variant has been reported in association with cutis laxa and in control cohorts (Hu et al., 2006; Lotery et al., 2006). Hu et al. (2006) reported G202R was paternally inherited in a patient with cutis laxa, who also harbored compound heterozygous variants in the ELN gene (Hu et al., 2006). Lotery et al. (2006) identified G202R in 1/188 healthy British control individuals. Additionally, this variant was observed in 24/11,570 (0.2%) Latino alleles in the Exome Aggregation Consortium data-set (Lek et al., 2016).The G202R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within an EGF-like calcium-binding domain where only amino acids with similar properties to Glycine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not G202R is damaging to the protein structure/function. Schneider et al. (2010) demonstrated that G202R did not affect the structure or calcium-binding properties of fibulin-5; however, it was proposed this variant may lead to susceptibility to cleavage by inflammatory proteases under certain conditions due to introduction of a novel proteolytic cleavage site. The authors conclude that, although G202R may not independently cause disease, it may increase susceptibility to disease (Schneider et al., 2010). Similarly, Jones et al. (2010) demonstrated the G202R variant, identified in a control subject, increases binding to tropoelastin and concluded G202R is functionally different from wild-type, but not sufficient to cause disease. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
GeneReviews RCV000020641 SCV000041162 pathologic Autosomal recessive cutis laxa type IA 2011-10-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000316304 SCV000389475 likely benign Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000375520 SCV000389476 likely benign Cutis Laxa, Dominant/Recessive 2016-06-14 criteria provided, single submitter clinical testing

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