ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7661G>A (p.Arg2554Gln)

gnomAD frequency: 0.00014  dbSNP: rs199522781
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000382117 SCV000392124 likely benign Acromicric dysplasia 2017-04-28 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 Laboratory Services, Illumina RCV000290065 SCV000392125 likely benign Familial thoracic aortic aneurysm and aortic dissection 2017-04-28 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 Laboratory Services, Illumina RCV000347326 SCV000392126 likely benign Marfan syndrome 2017-04-28 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 Laboratory Services, Illumina RCV000396029 SCV000392127 likely benign Weill-Marchesani syndrome 2017-04-28 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 Laboratory Services, Illumina RCV000313030 SCV000392128 likely benign Ectopia lentis 1, isolated, autosomal dominant 2017-04-28 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 Laboratory Services, Illumina RCV000400646 SCV000392130 likely benign Stiff skin syndrome 2017-04-28 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 Laboratory Services, Illumina RCV000297567 SCV000392131 likely benign Geleophysic dysplasia 2017-04-28 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000454621 SCV000539149 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2/3 papers in HGMD classify as VUS; ExAC: 0.1% (7/6278) Finnish chromosomes
GeneDx RCV000766961 SCV000616717 uncertain significance not provided 2024-04-11 criteria provided, single submitter clinical testing Identified in patients with Marfan syndrome in published literature (PMID: 32679894, 21883168); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25812041, 24941995, 27153395, 27647783, 29168297, 21883168, 12938084, 32679894)
Labcorp Genetics (formerly Invitae), Labcorp RCV001081111 SCV000753169 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-12-22 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000290065 SCV001347317 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-06-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 2554 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three young individuals affected with Marfan syndrome (PMID: 32679894). This variant has also been observed in an individual with features of Marfan syndrome, but the individual did not meet Ghent criteria (PMID: 21883168). This variant has been identified in 43/281648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000454621 SCV003844596 likely benign not specified 2023-02-13 criteria provided, single submitter clinical testing Variant summary: FBN1 c.7661G>A (p.Arg2554Gln) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of 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 0.00015 in 281648 control chromosomes (gnomAD), predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.7661G>A has been reported in the literature in individuals affected with Marfan Syndrome without strong evidence for causality (Sheikhzadeh_2012, Stark_2020). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health RCV000347326 SCV004816748 uncertain significance Marfan syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 2554 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three young individuals affected with Marfan syndrome (PMID: 32679894). This variant has also been observed in an individual with features of Marfan syndrome, but the individual did not meet Ghent criteria (PMID: 21883168). This variant has been identified in 43/281648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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