chr15-48445467-G-T

Position:

• chr15-48445467-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM6_Supporting PVS1 PP4 PP1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.5826C>A, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with infantile Marfan syndrome (MFS) and was found to be de novo without confirmation of parental relationships (internal data, PP4, PM6_Supporting). This variant has been reported 7 times in ClinVar, twice as pathogenic and five times as uncertain significance (Variantion ID: 547334). At least three other probands with clinical features of MFS carry the same variant (PMID 12068374, 22772377, Centre for Human Genetics ClinVar entry, PS4_Sup). In one family with features of MFS, including mitral valve prolapse, striae, pectus carinatum, scoliosis, striae, joint hypermobility, and wrist and thumb sign, this variant was found to segregate with disease in four affected family members (PMID 12068374, PP1). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4_Sup, PM2_Sup, PM6_Sup, PP1, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA269532860/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:5
• Conservation: PhyloP100: 4.10

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.5826C>A	p.Cys1942*	stop_gained	48/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5826C>A	p.Cys1942*	stop_gained	47/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5826C>A	p.Cys1942*	stop_gained	48/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Feb 22, 2024	The NM_00138 c.5826C>A, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with infantile Marfan syndrome (MFS) and was found to be de novo without confirmation of parental relationships (internal data, PP4, PM6_Supporting). This variant has been reported 7 times in ClinVar, twice as pathogenic and five times as uncertain significance (Variantion ID: 547334). At least three other probands with clinical features of MFS carry the same variant (PMID 12068374, 22772377, Centre for Human Genetics ClinVar entry, PS4_Sup). In one family with features of MFS, including mitral valve prolapse, striae, pectus carinatum, scoliosis, striae, joint hypermobility, and wrist and thumb sign, this variant was found to segregate with disease in four affected family members (PMID 12068374, PP1). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4_Sup, PM2_Sup, PM6_Sup, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 09, 2021	The p.C1942* pathogenic mutation (also known as c.5826C>A), located in coding exon 47 of the FBN1 gene, results from a C to A substitution at nucleotide position 5826. This changes the amino acid from a cysteine to a stop codon within coding exon 47. This variant was reported in a family with features of Marfan syndrome, including ascending aortic aneurysms, pectus abnormalities, scoliosis, contractures, hypermobility, and myopia (Schrijver I et al. Am J Hum Genet, 2002 Aug;71:223-37). 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. -

Stiff skin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Weill-Marchesani syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Acromicric dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Ectopia lentis 1, isolated, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.96
GERP RS		4.8

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: rs363806; hg19: chr15-48737664;