Submissions for variant NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn)

dbSNP: rs794728208

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000659532	SCV005387653	pathogenic	Marfan syndrome	2024-05-23	reviewed by expert panel	curation	The NM_00138 c.3712G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1238 (p.Asp1238Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 12 times in ClinVar: three times as pathogenic, eight times as likely pathogenic, and once as uncertain significance (Variation ID: 200022). This variant has also been reported in multiple individuals with a clinical diagnosis of MFS, ectopia lentis and/or clinical features of MFS (PS4_Strong; PMID 32730690, 10533071, 30675029, internal lab data). This variant was found to segregate with disease in at least four affected relatives with MFS from four families (PMID 32730690, internal lab data; PP1_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3713A>G (p.Asp1238Gly), has previously been previously established as (likely) pathogenic and was reported an individual with a clinical diagnosis of MFS (PM5; PMID 11175294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.895). This variant is located in the last nucleotide of the exon. In silico prediction programs suggest a possibly impact on splicing, however RNA analysis using patient blood showed no impact for this variant on RNA splicing (PMID 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Strong, PM1, PM5, PP1_Mod, PM2_Sup, PP2, PP3, PP4.
GeneDx	RCV000181493	SCV000233796	likely pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Reported in association with Marfan syndrome and/or TAAD (Yuan et al., 1999; Hicks et al., 2019; Renner et al., 2019; Cope et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In vitro RT-PCR and transcriptome-wide blood RNA sequencing demonstrated that p.(D1238N) results in normal splicing (Wai et al., 2020); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 20886638, 29510914, 30675029, 32730690, 32123317, 34135346, 10533071, 36945115)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659532	SCV000781359	likely pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763355	SCV000894045	pathogenic	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	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000659532	SCV000897663	pathogenic	Marfan syndrome	2018-11-20	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000181493	SCV000927424	likely pathogenic	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808826	SCV000948948	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1238 of the FBN1 protein (p.Asp1238Asn). This variant also falls at the last nucleotide of exon 30, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 10533071; Invitae). ClinVar contains an entry for this variant (Variation ID: 200022). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001176349	SCV001340313	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-02-06	criteria provided, single submitter	clinical testing	This variant replaces aspartate with asparagine at codon 1238 in calcium-binding EGF-like motif 20 (a.a. 1238 - 1279) of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant alters the last nucleotide of the exon, which is part of the 5' splice region. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing, while an RNA study has shown that this variant does not change RNA splicing (PMID: 3212331). This variant has been reported in four individuals affected with Marfan syndrome (PMID: 10533071, 30675029, 32730690, ClinVar SCV000948948.4) and in two individuals affected with aortic aneurysms and dissections (PMID: 29510914, Color internal data). It has also been observed in an asymptomatic individual (PMID: 34135346). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192801	SCV001361161	uncertain significance	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3712G>A (p.Asp1238Asn) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the last 3' position of exon 30, therefore, suggesting the variant could affect splicing. Several computational tools predict a suggestive impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3712G>A has been reported in the literature in individuals affected with Marfan Syndrome and aortopathies and related disorders of connective tissue (De Cario_2018, Yuan_1999, Renner_2019). Hicks_2018 reports a 15 y/o female that presented with no phenotypic representation, however, had a family history. 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. However, HGMD reports another missense variant at this location, D1238N, associated with Marfan syndrome. Seven ClinVar submissions (evaluation after 2014) cites the variant three times as pathogenic, three times as likely pathogenic, and once as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000181493	SCV001450216	likely pathogenic	not provided	2017-03-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176349	SCV002041976	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-04-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001176349	SCV002624950	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-11-01	criteria provided, single submitter	clinical testing	The p.D1238N variant (also known as c.3712G>A), located in coding exon 29 of the FBN1 gene, results from a G to A substitution at nucleotide position 3712. The amino acid change results in aspartic acid to asparagine, an amino acid with highly similar properties at codon. However, this change occurs in the last base pair of coding exon 29, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in numerous individuals with phenotypes consistent with a Marfan syndrome diagnosis, including segregating with disease in some families (Yuan B et al. Hum. Mutat., 1999;14:440-6; Renner S et al. Genet Med, 2019 08;21:1832-1841; Cope H et al. Mol Genet Genomic Med, 2020 10;8:e1397; external communication; Ambry internal data). This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000659532	SCV000786990	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing