NM_000138.5:c.494G>C

Variant names:

• chr15-48596327-C-G
• rs1060501079
• NM_000138.5:c.494G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000138.5(FBN1):​c.494G>C​(p.Arg165Pro) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.57

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 10 ACMG points.

• PM1: In a disulfide_bond (size 12) in uniprot entity FBN1_HUMAN there are 8 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 the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.953
• PP5: Variant 15-48596327-C-G is Pathogenic according to our data. Variant chr15-48596327-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406352.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.494G>C	p.Arg165Pro	missense_variant	Exon 6 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.494G>C	p.Arg165Pro	missense_variant	Exon 5 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.494G>C	p.Arg165Pro	missense_variant	Exon 6 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.494G>C	p.Arg165Pro	missense_variant	Exon 6 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.494G>C		non_coding_transcript_exon_variant	Exon 6 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.494G>C		non_coding_transcript_exon_variant	Exon 6 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.494G>C		non_coding_transcript_exon_variant	Exon 6 of 68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 165 of the FBN1 protein (p.Arg165Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome and/or Marfan syndrome (PMID: 31279624; Invitae). ClinVar contains an entry for this variant (Variation ID: 406352). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg165 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

May 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R165P variant of uncertain significance in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. The R165P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, although the R165P variant is within an EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue, as the majority of pathogenic missense changes associated with Marfan syndrome do (Collod-Beroud et al., 2003).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Vest4		0.91
MutPred		0.59		Gain of catalytic residue at C168 (P = 0.2222);
MVP		0.98
MPC		1.8
ClinPred		0.99	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1060501079; hg19: chr15-48888524;