15-48610775-C-T

Variant names:

• chr15-48610775-C-T
• rs397515782
• NM_000138.5:c.299G>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.299G>A​(p.Cys100Tyr) 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. 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. C100F) 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: 7.48

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a disulfide_bond (size 11) in uniprot entity FBN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr15-48610775-C-A is described in Lovd as [Likely_pathogenic].
• 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 MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 15-48610775-C-T is Pathogenic according to our data. Variant chr15-48610775-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48610775-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.299G>A	p.Cys100Tyr	missense_variant	Exon 4 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.299G>A	p.Cys100Tyr	missense_variant	Exon 3 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.299G>A	p.Cys100Tyr	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.299G>A	p.Cys100Tyr	missense_variant	Exon 4 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.299G>A		non_coding_transcript_exon_variant	Exon 4 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.299G>A		non_coding_transcript_exon_variant	Exon 4 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.299G>A		non_coding_transcript_exon_variant	Exon 4 of 68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Feb 04, 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.Cys100Tyr variant in FBN1 has been identified in 1 African American indivi dual with Marfan syndrome, 1 Chinese individual with Marfan syndrome, and segreg ated with disease in 1 affected relative (LMM unpublished data, Chung 2009). It was absent from large population studies. Additionally, another variant at the s ame position (p.Cys100Phe) has been identified to occur de novo in 1 Asian indiv idual with Marfan syndrome (LMM unpublished data), suggesting that a change at t his position may not be tolerated. Computational prediction tools and conservati on analysis suggest that the p.Cys100Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermor e, this variant affects a highly conserved cysteine residue in the EGF-like doma ins, which is a common finding in individuals with Marfan syndrome (Schrijver 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Cys100Tyr variant is likely pathogenic. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay are commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects are associated with Marfan syndrome and ectopia lentis (MIM#129600; OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant affects a well-established functional cysteine residue of an EGF-like domain. Cysteine substitutions in EGF-like domains are commonly disease-causing (PMID: 31227806). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to phenylalanine and arginine have been described as pathogenic or likely pathogenic in ClinVar and the literature (PMID: 31730815). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported likely pathogenic in ClinVar and in the literature in an individual with Marfan syndrome (PMID: 19533785). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Mother does not have the variant. Father was not tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

May 21, 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 tyrosine, which is neutral and polar, at codon 100 of the FBN1 protein (p.Cys100Tyr). 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: 19533785; Invitae). ClinVar contains an entry for this variant (Variation ID: 228262). 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). 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	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.85		Loss of disorder (P = 0.0664);
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397515782; hg19: chr15-48902972;