NM_000138.5:c.493C>T

Variant names:

• chr15-48596328-G-A
• rs113905529
• NM_000138.5:c.493C>T

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.493C>T​(p.Arg165*) variant causes a stop gained change. 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:7
• Conservation: PhyloP100: 4.96

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 15-48596328-G-A is Pathogenic according to our data. Variant chr15-48596328-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.493C>T	p.Arg165*	stop_gained	Exon 6 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.493C>T	p.Arg165*	stop_gained	Exon 5 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.493C>T	p.Arg165*	stop_gained	Exon 6 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.493C>T	p.Arg165*	stop_gained	Exon 6 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.493C>T		non_coding_transcript_exon_variant	Exon 6 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.493C>T		non_coding_transcript_exon_variant	Exon 6 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.493C>T		non_coding_transcript_exon_variant	Exon 6 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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000042373). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 22, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg165X variant has previously been reported in 3 individuals with clinical features of Marfan syndrome (Rybczynski 2008, Rommel 2005, Soylen 2009). In addi tion, this variant has been identified in 3 other unrelated probands tested by o ur laboratory and cosegregates with clinical features in two families. This nons ense variant leads to a premature termination codon at position 165, which is pr edicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) bas ed upon predicted effect on the protein, presence in symptomatic individuals and segregation in symptomatic family members. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Oct 04, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R165* pathogenic mutation (also known as c.493C>T), located in coding exon 5 of the FBN1 gene, results from a C to T substitution at nucleotide position 493. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been previously reported in individuals with clinical features of Marfan syndrome (Rommel K et al. Hum Mutat. 2005;26(6):529-39; Rybczynski M et al. Am J Med Genet. 2008;146A(24):3157-66; Söylen B et al. Clin Genet. 2009;75(3):265-70). 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. -

Isolated thoracic aortic aneurysm Pathogenic:1

Sep 01, 2018

Department of Vascular Biology, Beijing Anzhen Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Jun 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19012347, 25525159, 16220557, 25101912, 31279664, 31536524, 29357934, 33824467, 31098894, 19159394) -

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

Dec 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg165*) 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 individuals with Marfan syndrome (PMID: 16220557, 19159394, 25101912). ClinVar contains an entry for this variant (Variation ID: 42373). 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	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.93
GERP RS		4.9

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: rs113905529; hg19: chr15-48888525;