chr15-48600213-C-T

Variant names:

• chr15-48600213-C-T
• rs397515794
• NM_000138.5:c.368G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.368G>A​(p.Cys123Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a disulfide_bond (size 10) in uniprot entity FBN1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.996
• PP5: Variant 15-48600213-C-T is Pathogenic according to our data. Variant chr15-48600213-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48600213-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.368G>A	p.Cys123Tyr	missense_variant	Exon 5 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.368G>A	p.Cys123Tyr	missense_variant	Exon 4 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.368G>A	p.Cys123Tyr	missense_variant	Exon 5 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.368G>A	p.Cys123Tyr	missense_variant	Exon 5 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.368G>A		non_coding_transcript_exon_variant	Exon 5 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.368G>A		non_coding_transcript_exon_variant	Exon 5 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.368G>A		non_coding_transcript_exon_variant	Exon 5 of 68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461492 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Jun 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Cys123Tyr variant has been reported in 3 individuals with a clinical diagnos is of or suspected Marfan syndrome and was absent from 220 control chromosomes ( Arbustini 2005, D'Amore 2005, Attanasio 2008). In addition, this variant affects a cysteine residue. Cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999). The Cys123Tyr variant also lies within a functional domain of FBN1 and is likely to be responsible for the clinical featu res observed in this individual. Therefore, this variant is highly likely to be pathogenic. -

FBN1-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.368G>A variant is predicted to result in the amino acid substitution p.Cys123Tyr. This variant has been reported in multiple individuals with Marfan syndrome (Arbustini et al. 2005. PubMed ID: 16222657; Attanasio et al. 2008. PubMed ID: 18435798; Zadeh et al. 2011. PubMed ID: 21932315). Alternate substitutions of this amino acid residue (p.Cys123Phe, p.Cys123Arg, p.Cys123Gly) have been reported in individuals with Marfan syndrome (Table S1, Guo et al. 2024. PubMed ID: 38190127; Groth et al. 2017. PubMed ID: 27906200; Table S1, Groth et al. 2017. PubMed ID: 27906200). Cysteine residues in this region of FBN1 are known to be critical for formation of disulfide bonds within the protein (Mellody et al. 2006. PubMed ID: 16905551). This variant is absent in the large population database gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic. -

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

May 05, 2023

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 123 of the FBN1 protein (p.Cys123Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FBN1-related conditions (PMID: 16222657, 18435798, 21932315). ClinVar contains an entry for this variant (Variation ID: 42340). 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. 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. -

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

Dec 29, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in at least 4 individuals with clinical suspicion or diagnoses of Marfan syndrome, with ectopia lentis noted in each patient (D'Amore 2005 PMID: 15983637; Arbustini 2005 PMID: 16222657; Attanasio 2008 PMID: 18435798; Zadeh 2011 PMID: 21932315). This variant is absent from gnomAD. It is present in ClinVar, with the only submitting laboratory classifying it as pathogenic (Variation ID: 42340). This variant alters a cysteine residue in an EGF-like domain of the encoded protein; cysteine residues in EGF-like and cbEGF-like domains of the fibrillin-1 protein are well-established as important for protein structure and function (Robinson 2006 PMID: 16571647; Faivre 2007 PMID: 17701892). Evolutionary conservation and computational prediction tools strongly support that this variant impacts the protein. Other variants at this same amino acid position (p.Cys123Arg, p.Cys123Gly) have also been reported in association with disease (Zhou 2021 PMID: 33576469; Li 2019 PMID: 31098894), further supporting the functional importance of the wild-type residue. In summary, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		1.0
MutPred		1.0		Loss of disorder (P = 0.0994);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs397515794; hg19: chr15-48892410;