rs397515867

Positions:

• chr15-48526159-T-TA

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.958dupT​(p.Tyr320fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.23

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 15-48526159-T-TA is Pathogenic according to our data. Variant chr15-48526159-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 42448.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.958dupT	p.Tyr320fs	frameshift_variant	9/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.958dupT	p.Tyr320fs	frameshift_variant	8/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.958dupT	p.Tyr320fs	frameshift_variant	9/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.958dupT		non_coding_transcript_exon_variant	9/67	1		ENSP00000453958.2
FBN1	ENST00000674301.2	n.958dupT		non_coding_transcript_exon_variant	9/68			ENSP00000501333.2
FBN1	ENST00000537463.6	n.636+11551dupT		intron_variant		5		ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2012

The Tyr320fs variant has not been reported in the literature nor previously iden tified by our laboratory. This frameshift variant is predicted to alter the pro tein?s amino acid sequence beginning at position 320 and lead to a premature ter mination codon 28 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Loss of function of the FBN1 gene is an es tablished disease mechanism in Marfan syndrome. Therefore, this variant meets ou r criteria to be classified as pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2020

The c.958dupT pathogenic mutation, located in coding exon 8 of the FBN1 gene, results from a duplication of T at nucleotide position 958, causing a translational frameshift with a predicted alternate stop codon (p.Y320Lfs*28). 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

Feb 29, 2024

Variant summary: FBN1 c.958dupT (p.Tyr320LeufsX28) 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 was absent in 251444 control chromosomes. c.958dupT has been reported in the literature in association with Marfan Syndrome (Groth_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27906200). ClinVar contains an entry for this variant (Variation ID: 42448). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs397515867; hg19: chr15-48818356;