rs112645512

Positions:

• chr15-48516225-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.1285C>T​(p.Arg429Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.40

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48516225-G-A is Pathogenic according to our data. Variant chr15-48516225-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1285C>T	p.Arg429Ter	stop_gained	11/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1285C>T	p.Arg429Ter	stop_gained	10/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1285C>T	p.Arg429Ter	stop_gained	11/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.1285C>T	p.Arg429Ter	stop_gained, NMD_transcript_variant	11/67	1
FBN1	ENST00000674301.2	c.1285C>T	p.Arg429Ter	stop_gained, NMD_transcript_variant	11/68
FBN1	ENST00000537463.6	c.636+21486C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, 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 rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic/likely pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	May 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Heart Medical Centre, First Affiliated Hospital of Gannan Medical University	Dec 28, 2021	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

The p.R429* pathogenic mutation (also known as c.1285C>T), located in coding exon 10 of the FBN1 gene, results from a C to T substitution at nucleotide position 1285. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in several unrelated individuals with classical Marfan syndrome and in one study had confirmed segregation with disease (Matyas G et al. Hum Mutat. 2002;19(4):443-456; Rommel K et al. Hum Mutat. 2002;20(5):406-407; Baudhuin LM et al. J. Hum. Genet., 2015 May;60:241-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 02, 2024

Variant summary: FBN1 c.1285C>T (p.Arg429X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251556 control chromosomes. c.1285C>T has been reported in the literature in individuals affected with Marfan Syndrome (example, Matyas_2002, Rommel_2002, Collod-Beroud_2003, Rommel_2005, Sakai_2006, Attanasio_ 2008, Magyar_2009, Stheneur_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11933199, 12402346, 12938084, 16220557, 16835936, 18435798, 19293843, 19618372). ClinVar contains an entry for this variant (Variation ID: 180351). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 03, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 180351; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19293843, 31098894, 27611364, 19618372, 25101912, 12402346, 18435798, 25525159, 11933199, 16835936) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180351). This premature translational stop signal has been observed in individuals with Marfan syndrome or suspected Marfan syndrome (PMID: 12402346, 16835936, 18435798, 19618372, 27234404). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg429*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		2.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs112645512; hg19: chr15-48808422;