ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8176C>T (p.Arg2726Trp) (rs61746008)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000029787 SCV000190196 likely benign Marfan syndrome 2015-12-01 criteria provided, single submitter research
GeneDx RCV000243696 SCV000233931 likely benign not specified 2017-11-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001081571 SCV000283655 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-11-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000243696 SCV000302591 likely benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000617106 SCV000317338 uncertain significance Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586191 SCV000343601 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394448 SCV000392084 likely benign Stiff skin syndrome 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000279856 SCV000392085 likely benign Acromicric dysplasia 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000337198 SCV000392086 likely benign Geleophysic dysplasia 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000029787 SCV000392087 likely benign Marfan syndrome 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000181628 SCV000392088 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000399653 SCV000392090 likely benign Ectopia lentis, isolated, autosomal dominant 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000306003 SCV000392091 likely benign Weill-Marchesani syndrome 2018-11-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000029787 SCV000493742 uncertain significance Marfan syndrome 2016-04-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000243696 SCV000695620 likely benign not specified 2019-11-04 criteria provided, single submitter clinical testing Variant summary: FBN1 c.8176C>T (p.Arg2726Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 252730 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.8176C>T has been reported in the literature in individuals affected with Marfan Syndrome, as well as in mildly affected and unaffected family members, suggesting incomplete penetrance, or a mostly benign nature. Since the penetrance of Marfan Syndrome (0.71) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Co-occurrences with other pathogenic FBN1 variants have been reported (e.g. Stheneur 2009: c.3299G>T (p.Gly1100V), c.6388G>A (p.Glu2130Lys), c.1416C>A (p.Cys472X); Arnaud 2017: c.1585C>T (Arg529X), c.6388G>A (p.Glu2130Lys); Becerra-Munoz 2018: c.7754T>C, (p.Ile2585Thr); and in an internal sample: c.3073_3074insA (p.Phe1025fsX7)), providing supporting evidence for a benign role. Some publications also reported experimental evidence evaluating an impact on protein function, showing a decreased protein processing (C-terminal propeptide cleavage) (Milewicz 1995, Lonnqvist 1998). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics RCV000029787 SCV000807280 uncertain significance Marfan syndrome 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as causing Marfanoid-like features. It has been found 13 times in our laboratory, always inherited when parents are tested, and not always in patients with Marfanoid features.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000181628 SCV000902108 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-09-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000181628 SCV000911061 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-04-25 criteria provided, single submitter clinical testing
Mendelics RCV000029787 SCV001139585 likely benign Marfan syndrome 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000029787 SCV000038187 uncertain significance Marfan syndrome 2009-01-01 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000029787 SCV000787402 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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