rs397515847

Variant names:

• chr15-48427603-A-G
• rs397515847
• NM_000138.5:c.7168T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-48427603-A-G
• chr15-48427603-A-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.7168T>C​(p.Cys2390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2390S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48427603-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 690431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 15-48427603-A-G is Pathogenic according to our data. Variant chr15-48427603-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7168T>C	p.Cys2390Arg	missense_variant	Exon 58 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7168T>C	p.Cys2390Arg	missense_variant	Exon 57 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7168T>C	p.Cys2390Arg	missense_variant	Exon 58 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Nov 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys2390Arg variant in FBN1 has been identified by our laboratory in 1 adul t with Marfan syndrome and segregated with disease in 2 affected children. It wa s absent from large population studies. A different amino acid change at the sam e position (p.Cys2390Ser) has been reported in one individual with clinical feat ures of Marfan syndrome (Rand-Hendriksen 2007), suggesting that a change at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. While cysteine subsituti ons are a common finding in individuals with Marfan syndrome (Schrijver 1999), t his variant is not located within the conserved cystein residues of the EGF-like domain. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys2390Arg variant is likely pathogenic. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

May 31, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.7168T>C (p.Cys2390Arg) results in a non-conservative amino acid change located in the TB domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant affects a Cysteine, which "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." This variant is not located within the conserved cystein residues of the EGF-like domain, however, cysteine subsitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999) and are listed as one of the criteria for causal FBN1 mutation (Loeys_2010). The variant was absent in 245812 control chromosomes (gnomAD). The variant, c.7168T>C, has not been reported in the literature in individuals affected with Marfan Syndrome but it has been observed in three affected individuals (1 adult with Marfan syndrome and segregated with disease in 2 affected children) tested in another clinical lab. Another variant, c.7168T>A, which affects the same Cysteine, Cys2390Ser has been reported in an affected MFS pt (Rand-Hendrikson_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Feb 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2390 of the FBN1 protein (p.Cys2390Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 33059708; Invitae). ClinVar contains an entry for this variant (Variation ID: 42421). 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 with a positive predictive value of 95%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant disrupts the p.Cys2390 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17663468), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Vest4		0.99
MutPred		0.94		Gain of MoRF binding (P = 0.04);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515847; hg19: chr15-48719800;