rs193922239

Positions:

• chr15-48415708-C-G
• chr15-48415708-C-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.7879G>C​(p.Gly2627Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.91

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 21 ACMG points.

• PS1: Transcript NM_000138.5 (FBN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a disulfide_bond (size 14) in uniprot entity FBN1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 15-48415708-C-G is Pathogenic according to our data. Variant chr15-48415708-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48415708-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7879G>C	p.Gly2627Arg	missense_variant	64/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7879G>C	p.Gly2627Arg	missense_variant	63/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7879G>C	p.Gly2627Arg	missense_variant	64/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 02, 2024

Variant summary: FBN1 c.7879G>C (p.Gly2627Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251378 control chromosomes (gnomAD). c.7879G>C has been reported in the literature in at least an individual affected with Marfan Syndrome (example: Hung_2009). In addition, a different nucleotide change at the cDNA level (c.7879G>A) leading to the same amino acid change (i.e. p.Gly2627Arg), was detected in a compound heterozygote Marfan syndrome child who had a very severe form of MFS resulting in death from cardiac failure at the age of 4 months. The mother of the child was heterozygous for the variant and was affected with Marfan syndrome. Biochemical studies of fibroblast cultures from the child and both parents pointed to a severely disturbed assembly of microfibrils (Karttunen_1994). These data together indicate that the c.7879G>C variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7977366, 19839986). ClinVar contains an entry for this variant (Variation ID: 372606). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest G2627R exerts a damaging effect to the biosynthesis and secretion of profibrillin (Karttunen et al., 1994); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Reported in ClinVar (ClinVar Variant ID# 372606; Landrum et al., 2016); Located at a residue involved in domain packing and predicted to alter interaction of calcium-binding EGF-like domains (Downing et al., 1996); Same missense substitution due to a different nucleotide change (c.7879 G>A) reported in an infant with severe manifestation of Marfan syndrome and biallelic variants in the FBN1 gene; the heterozygous parent had milder features of Marfan syndrome (Karttunen et al., 1994); This variant is associated with the following publications: (PMID: 10633129, 8653794, 31098894, 19839986, 7977366) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2018

This variant has been reported in heterozygosis in individuals affected with Marfan syndrome (PMID: 19839986, Invitae) and in compound heterozygosis with a rare missense variant in an individual with Marfan syndrome whose parents (heterozygotes) were mildly affected (PMID: 7977366). ClinVar contains an entry for this variant (Variation ID: 372606). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies in fibroblasts, from individuals with this variant, have shown that this missense change may affect protein processing and interfere with myofibrils structure (PMID: 7977366). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 2627 of the FBN1 protein (p.Gly2627Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Marfan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Nov 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.99
Sift	Benign	0.042	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.99
MutPred		0.95		Loss of ubiquitination at K2630 (P = 0.079);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8

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: rs193922239; hg19: chr15-48707905;