ClinVar Miner

Submissions for variant NM_006329.3(FBLN5):c.268G>A (p.Gly90Ser) (rs144288844)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000202614 SCV000389483 uncertain significance Age-related macular degeneration 3 2018-03-06 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000521928 SCV000617418 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing The G90S variant in the FBLN5 gene has previously been reported in two siblings with spinal Charcot-Marie-Tooth as well as three of their relatives who were mildly affected with neurological and/or connective tissue involvement (Auer-Grumbach et al., 2011). G90S was also identified in a patient with age-related macular degeneration from age 79, mild to moderate weakness and wasting in hand and foot muscles, and axonal neuropathy in upper and lower limbs; this patient shared multiple single nucleotide polymorphism markers with the two siblings, suggesting a possible founder effect (Auer-Grumbach et al., 2011). The G90S 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 that is conserved in mammals. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, this variant was observed in 71/124,250 (0.06%) alleles from individuals of European (non-Finnish) ancestry and in 22/10,142 (0.2%) alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000521928 SCV001198603 uncertain significance not provided 2019-03-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 90 of the FBLN5 protein (p.Gly90Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs144288844, ExAC 0.08%). This variant has been observed in individuals affected with the FBLN5-related conditions (PMID: 21576112). ClinVar contains an entry for this variant (Variation ID: 218359). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001121879 SCV001280534 benign Cutis laxa 2018-03-06 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
OMIM RCV000202614 SCV000257548 pathogenic Age-related macular degeneration 3 2011-06-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV001249315 SCV001423279 not provided Autosomal recessive cutis laxa type IA; Cutis laxa, autosomal dominant 2 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 10-29-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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