rs1060501100

Positions:

• chr15-48534136-AAAGACCC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.799_805del, is a frameshift variant in FBN1 and is predicted to result in a premature stop codon at position 327. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was reported a pathogenic once in ClinVar (Variation ID: 406374). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614686/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.799_805delGGGTCTT	p.Gly267fs	frameshift_variant	8/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.799_805delGGGTCTT	p.Gly267fs	frameshift_variant	7/65		NP_001393645.1
FBN1	NM_001406717.1	c.799_805delGGGTCTT	p.Gly267fs	frameshift_variant	8/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.799_805delGGGTCTT	p.Gly267fs	frameshift_variant	8/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.799_805delGGGTCTT		non_coding_transcript_exon_variant	8/67	1		ENSP00000453958.2
FBN1	ENST00000674301.2	n.799_805delGGGTCTT		non_coding_transcript_exon_variant	8/68			ENSP00000501333.2
FBN1	ENST00000537463.6	n.636+3568_636+3574delGGGTCTT		intron_variant		5		ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Jun 15, 2023

The NM_00138 c.799_805del, is a frameshift variant in FBN1 and is predicted to result in a premature stop codon at position 327. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was reported a pathogenic once in ClinVar (Variation ID: 406374). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406374). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly267Leufs*61) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501100; hg19: chr15-48826333;