chr15-48644769-T-G

Variant names:

• chr15-48644769-T-G
• rs730880097
• NM_000138.5:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.1A>C​(p.Met1?) variant causes a initiator codon 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 Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 initiator_codon
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.95
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 86 pathogenic variants. Next in-frame start position is after 99 codons. Genomic position: 48610779. Lost 0.034 part of the original CDS.
• PS1: Another start lost variant in NM_000138.5 (FBN1) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48644769-T-G is Pathogenic according to our data. Variant chr15-48644769-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 495569.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9		NP_001393646.1
FBN1	NM_001406718.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 3		NP_001393647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Sep 26, 2023

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000138.5 c.1A>C alters the methionine at amino acid position 1, which functions as the translation initiation codon, and is considered a start-loss variant. This is expected to result in an absent or disrupted protein product due to loss of protein translation, N-terminal truncation, or alteration of the reading frame (PVS1_moderate). Start-loss variants have been reported in the literature in at least 6 individuals with features suggestive of Marfan syndrome and in 1 individual with a clinical diagnosis of Marfan syndrome (PS4; PMIDs: 19012347, 19159394, 27611364, 29357934, 28973303, 29848614, 35058154). In one of these individuals with a non-specific phenotype and in another with a phenotype consistent with FBN1 but not highly specific, a start-loss variant was found to be de novo with maternity and paternity unconfirmed (PM6; PMIDs: 28973303, 35058154). A start-loss variant was also identified in an internal family of 2 siblings with clinical diagnoses of Marfan syndrome (PP4; Bichat). This specific variant has been reported in ClinVar as pathogenic and likely pathogenic (Variation ID: 495569). This variant and all other start-loss variants are absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). 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: PS4, PVS1_moderate, PM6, PM2_supporting, PP4. -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Nov 18, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the FBN1 gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Mutations in this codon have been reported in patients with Marfan syndrome (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Aug 10, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 234430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, other variants affecting p.Met1 (c.1A>T, c.1A>G, c.2T>A, c.3G>A) have been reported to associate with MFS. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.44	T
PhyloP100		4.0
PROVEAN	Benign	-0.50	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.65	T;D
Sift4G	Benign	0.40	T;D
Vest4		0.85
MutPred		0.98		Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);
MVP		0.97
ClinPred		0.91	D
GERP RS		4.6
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730880097; hg19: chr15-48936966;