15-48485374-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PS4PP1_ModeratePP4PP2PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014476/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.3712G>A | p.Asp1238Asn | missense_variant, splice_region_variant | Exon 30 of 66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.3712G>A | p.Asp1238Asn | missense_variant, splice_region_variant | Exon 29 of 65 | NP_001393645.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:5
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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. -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3
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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 1238. 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). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is 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. -
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 tools indicate that this variant has a deleterious impact on protein structure and function. 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 five individuals affected with Marfan syndrome (PMID: 10533071, 30675029, 32730690, 38190127; ClinVar SCV000948948.6) 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. -
not provided Pathogenic:3
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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) -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
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; internal data). 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. -
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
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not specified Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at