NM_000138.5:c.338C>G

Variant names:

• chr15-48610736-G-C
• rs869025403
• NM_000138.5:c.338C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4 PP2 PM2_Supporting PS4_Moderate PM1

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.338C>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 113 (p. Ser113Cys) within an EGF-like domain of the protein. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (Internal data, PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 222600). It has been reported in the literature in individuals with a clinical diagnosis or clinical features of Marfan syndrome (PMID 34281902, Invitae Clinvar entry, Blueprint Genetics ClinVar entry, internal data, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant protein function and structure (REVEL: 0.384). 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: PS4_Mod, PM1, PM2_Sup, PP2, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA353680/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 7.55
• 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: Likely_pathogenic. The variant received 7 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.
• PP4: 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.338C>G	p.Ser113Cys	missense_variant	Exon 4 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.338C>G	p.Ser113Cys	missense_variant	Exon 3 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.338C>G	p.Ser113Cys	missense_variant	Exon 4 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.338C>G	p.Ser113Cys	missense_variant	Exon 4 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.338C>G		non_coding_transcript_exon_variant	Exon 4 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.338C>G		non_coding_transcript_exon_variant	Exon 4 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.338C>G		non_coding_transcript_exon_variant	Exon 4 of 68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

May 18, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2023

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.338C>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 113 (p. Ser113Cys) within an EGF-like domain of the protein. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (Internal data, PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 222600). It has been reported in the literature in individuals with a clinical diagnosis or clinical features of Marfan syndrome (PMID 34281902, Invitae Clinvar entry, Blueprint Genetics ClinVar entry, internal data, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant protein function and structure (REVEL: 0.384). 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: PS4_Mod, PM1, PM2_Sup, PP2, PP4 -

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

Jan 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with cysteine at codon 113 of the FBN1 protein (p.Ser113Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. In summary, this variant is a rare missense change with uncertain impact on protein function. In the absence of confirmed functional or genetic evidence, at this time it has been classified as a Variant of Uncertain Significance. This variant generates a cysteine residue in a two-codon linker region between two epidermal-growth-factor (EGF)–like domains of the FBN1 protein. Cysteine residues in EGF-like domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine generating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). However, it is uncertain whether this variant would have the same effect because it does not lie within a defined EGF-like domain. This variant has been observed in an individual with clinical findings that are highly specific for Marfan syndrome (Invitae). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 222600). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.34	D
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.057	T
Vest4		0.70
MutPred		0.26		Loss of glycosylation at S113 (P = 0.0919);
MVP		0.87
MPC		1.4
ClinPred		0.93	D
GERP RS		5.1
Mutation Taster		=3/97	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: rs869025403; hg19: chr15-48902933;