Submissions for variant NM_000138.5(FBN1):c.719G>A (p.Arg240His)

dbSNP: rs768744583

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520382	SCV000616925	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Reported in two siblings with Marfan syndrome who also harbor a frameshift variant on the opposite allele (in trans); the p.(R240H) variant was inherited from the unaffected father (PMID: 19059503); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; 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); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27582083, 27437668, 31098894, 12938084, 34426522, 24941995, 19059503)
Ambry Genetics	RCV001170325	SCV000739799	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-25	criteria provided, single submitter	clinical testing	The p.R240H variant (also known as c.719G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 719. The arginine at codon 240 is replaced by histidine, an amino acid with highly similar properties. In one study, p.R240H was identified in two probands in one family in conjunction with the c.3861delC pathogenic FBN1 mutation. In this family, p.R240H was inherited from the unaffected father, and c.3861delC was inherited from the affected mother; however, the probands appeared to have a more severe clinical phenotype than their mother (Van Dijk FS et al. Eur J Med Genet. 2009;52(1):1-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691703	SCV000819493	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 240 of the FBN1 protein (p.Arg240His). This variant is present in population databases (rs768744583, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome. In at least one individual, this variant co-occurred with a pathogenic variant in the FBN1 gene. (PMID: 19059503; Invitae). ClinVar contains an entry for this variant (Variation ID: 449122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. 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.
Mendelics	RCV000989336	SCV001139624	uncertain significance	Marfan syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170325	SCV001332896	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170325	SCV001356395	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 240 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings affected with Marfan syndrome, who also carried a pathogenic truncation c.3861delC in the same gene (PMID: 19059503). Their affected mother carried the truncation variant, and this missense variant was inherited from unaffected father. This variant has been identified in 1/245956 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	RCV001358768	SCV001554639	uncertain significance	not specified	2021-03-25	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.719G>A (p.Arg240His) 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 was absent in 251226 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.719G>A has been reported in the literature in a family with Marfan Syndrome (van Dijk_2009). In this report, the two affected probands carried both the c.719G>A variant (inherited from their unaffected father) as well as the c.3861delC (inherited from their affected mother). While this suggests the truncating variant to be the causitive variant in this family, the authors note the c.719G>A variant may have a potentially modifying effect, as evidence by the probands having a more severe clinical phenotype than their mother (van Dijk_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002490899	SCV002776619	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	2021-10-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000520382	SCV004129821	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	FBN1: PM2, PP3, PP4
All of Us Research Program, National Institutes of Health	RCV000989336	SCV004823114	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 240 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings affected with Marfan syndrome, who also carried a pathogenic truncation c.3861delC in the same gene (PMID: 19059503). Their affected mother carried the truncation variant, and this missense variant was inherited from unaffected father. This variant has been identified in 1/245956 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.