rs1060501036

Variant names:

• chr15-48513599-C-A
• rs1060501036
• NM_000138.5:c.1538G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48513599-C-A
• chr15-48513599-C-G
• chr15-48513599-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1_Strong PP2 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_00138 c.1538G>T is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 513 (p.Cys513Phe). This variant has not been reported in the literature but has been found in at least two probands; this includes one individual with bilateral ectopia lentis and thoracic aortic aneurysm and dissection, and one with unspecified features of a connective tissue disorder (PS4_supporting; Invitae & LabCorp internal data, ClinVar Variation ID: 406288). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys513Gly, p.Cys513Ser, p.Cys513Tyr, p.Cys513Arg). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PM2_supporting, PS4_supporting, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614674/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1538G>T	p.Cys513Phe	missense_variant	Exon 13 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1538G>T	p.Cys513Phe	missense_variant	Exon 12 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1538G>T	p.Cys513Phe	missense_variant	Exon 13 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

Nov 16, 2023

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_00138 c.1538G>T is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 513 (p.Cys513Phe). This variant has not been reported in the literature but has been found in at least two probands; this includes one individual with bilateral ectopia lentis and thoracic aortic aneurysm and dissection, and one with unspecified features of a connective tissue disorder (PS4_supporting; Invitae & LabCorp internal data, ClinVar Variation ID: 406288). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys513Gly, p.Cys513Ser, p.Cys513Tyr, p.Cys513Arg). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PM2_supporting, PS4_supporting, PP2, PP3. -

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys513 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 27906200; Invitae), which suggests that this may be a clinically significant amino acid residue. 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). 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. ClinVar contains an entry for this variant (Variation ID: 406288). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 513 of the FBN1 protein (p.Cys513Phe). -

not specified Uncertain:1

May 15, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.1538G>T (p.Cys513Phe) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. "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)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. The variant was absent in 121218 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1538G>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MutPred		1.0		Loss of disorder (P = 0.0381);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501036; hg19: chr15-48805796; COSMIC: COSV105883614;