rs140630

Positions:

• chr15-48465580-G-A
• chr15-48465580-G-C
• chr15-48465580-G-T

Variant summary

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

The ENST00000316623.10(FBN1):​c.4930C>T​(p.Arg1644Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1644R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 ENST00000316623.10 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.77

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 15-48465580-G-A is Pathogenic according to our data. Variant chr15-48465580-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4930C>T	p.Arg1644Ter	stop_gained	40/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4930C>T	p.Arg1644Ter	stop_gained	39/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4930C>T	p.Arg1644Ter	stop_gained	40/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
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:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 11, 2022	This variant changes 1 nucleotide in exon 40 of the FBN1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten unrelated individuals affected with Marfan syndrome or related diseases (PMID: 11700157, 12068374, 17663468, 19839986, 24199744, 25652356, 25656438, 29768367, 31098894, 31536524). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2020	The p.R1644* pathogenic mutation (also known as c.4930C>T), located in coding exon 39 of the FBN1 gene, results from a C to T substitution at nucleotide position 4930. This changes the amino acid from an arginine to a stop codon within coding exon 39, located in the cbEGF-like #23 domain. This mutation has been reported as de novo in several patients with classic Marfan syndrome (Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637). This recurrent mutation has also been reported in familial cases (Rand-Hendriksen S et al. Am J Med Genet A. 2007;143A(17):1968-77; Pees C et al. Clin Genet. 2014;86(6):552-7, Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67), as well as detected in several Marfan syndrome patients in our laboratory (Ambry internal data). In addition to the clinical data, premature stop codons are typically deleterious in nature, as they are expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay, and in fact, quantitative assay for this mutation has shown reduced fibrillin synthesis and reduction of extracellular matrix deposition compared to normal control values (Schrijver I et al. Am J Hum Genet. 2002;71(2):223-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2017	The FBN1 c.4930C>T, p.Arg1644Ter variant (rs140630) has been reported in multiple individuals diagnosed with Marfan syndrome (Biggin 2004, Hung 2009, Loeys 2001, Schrijver 2002), and has been found as a de-novo alteration (Soylen 2009) or segregating with affected individuals in familial cases (Rand-Hendriksen 2007). RNA analysis of patient cells show no detectable transcripts generated from the variant allele, suggesting that the variant mRNA is subjected to nonsense mediated decay (Schrijver 2002). The variant is listed as pathogenic in ClinVar (Variation ID: 200186), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the p.Arg1644Ter variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2017	The R1644X pathogenic variant in the FBN1 gene has been published multiple times in association with Marfan syndrome (Loeys et al., 2001; Schrijver et al., 2002; Biggin et al., 2004; Arbustini et al., 2005; Rand-Hendriksen et al., 2007; Söylen et al., 2009; Pees et al., 2014). R1644X was reported as a de novo variant in two unrelated patients with Marfan syndrome, although maternity and paternity were not confirmed (Arbustini et al., 2005; Söylen et al., 2009). The R1644X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with Marfan syndrome or another FBN1-related disorder (Stenson et al., 2014). Furthermore, the R1644X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

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

Feb 26, 2018

Variant summary: FBN1 c.4930C>T (p.Arg1644X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 247204 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (2e-05 vs 0.00011), allowing no conclusion about variant significance. c.4930C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Biggin 2004, Hung 2009, Loeys 2001, Pees 2013, Rand-Hendriksen 2007, Schrijver 2002, Stheneur 2009, Franken 2016) including two de novo cases (Arbustini 2005, Soylen 2009), though paternity were not confirmed. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Schrijver 2002). The most pronounced variant effect results in 10%-<30% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Isolated thoracic aortic aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Arg1644*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 14695540, 16222657, 19159394, 24199744). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200186). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.98
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs140630; hg19: chr15-48757777; COSMIC: COSV57331556;