Submissions for variant NM_000138.5(FBN1):c.3389A>G (p.His1130Arg)

gnomAD frequency: 0.00003  dbSNP: rs747189975

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181484	SCV000233787	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Has been reported in a patient with Marfan syndrome; however, clinical and segregation data were not provided (Vatti et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; 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 (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 28941062, 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690524	SCV000818211	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781357	SCV000919333	uncertain significance	not specified	2018-12-03	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3389A>G (p.His1130Arg) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3389A>G has been reported in the literature in an individual with possible Marfan Syndrome (Vatti_2017). These report(s) 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001179626	SCV001344334	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1130 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with Marfan syndrome (PMID: 19533785, 28941062) and in another individual affected with cardiomyopathy (PMID: 32009526). This variant has been identified in 4/282878 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277441	SCV002566524	uncertain significance	Connective tissue disorder	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001179626	SCV002616235	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-11-23	criteria provided, single submitter	clinical testing	The p.H1130R variant (also known as c.3389A>G), located in coding exon 27 of the FBN1 gene, results from an A to G substitution at nucleotide position 3389. The histidine at codon 1130 is replaced by arginine, an amino acid with highly similar properties, and is located in the cbEGF-like #13 domain. This alteration has been reported in association with Marfan syndrome (Vatti L et al. Am. J. Med. Genet. A, 2017 Nov;173:2995-3002). Another alteration affecting the same amino acid, p.H1130P (c.3389A>C), has also been reported in association with Marfan syndrome (Chung BH et al. Am. J. Med. Genet. A, 2009 Jul;149A:1452-9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500529	SCV002781427	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996682	SCV004814812	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1130 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with Marfan syndrome (PMID: 19533785, 28941062) and in another individual affected with cardiomyopathy (PMID: 32009526). This variant has been identified in 4/282878 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.