rs201361628

chr15-48434633-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_000138.5(FBN1):c.6577G>A(p.Glu2193Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:2
• Conservation: PhyloP100: 4.98

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP6: Variant 15-48434633-C-T is Benign according to our data. Variant chr15-48434633-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255306.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=1, Benign=1}. Variant chr15-48434633-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.6577G>A	p.Glu2193Lys	missense_variant	54/66	ENST00000316623.10
FBN1	NM_001406716.1	c.6577G>A	p.Glu2193Lys	missense_variant	53/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.6577G>A	p.Glu2193Lys	missense_variant	54/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251226 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 08, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2023	This missense variant replaces glutamic acid with lysine at codon 2193 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with Marfan syndrome (PMID: 12938084, 27582083, Magyar 2011, dissertation, University of Zurich), in an individual with vascular anomalies (PMID: 28655553), and in a family with Parkinson's disease (Dheeraj, 2018). This variant has also been identified in 8/282630 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2023	The p.E2193K variant (also known as c.6577G>A), located in coding exon 53 of the FBN1 gene, results from a G to A substitution at nucleotide position 6577. The glutamic acid at codon 2193 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as homozygous in an individual with features of Marfan syndrome, including aortic dilatation and ectopia lentis, but clinical details were limited and additional family members were not evaluated (Arnaud P et al. J. Med. Genet., 2017 Feb;54:100-103). This alteration was also detected in one individual from a vascular anomalies cohort, but clinical details were not provided (Mattassi R et al. J Vasc Surg. 2018 03;67(3):922-932.e11). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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. -

Marfan syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces glutamic acid with lysine at codon 2193 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with Marfan syndrome (PMID: 12938084, 27582083, Magyar 2011, dissertation, University of Zurich), in an individual with vascular anomalies (PMID: 28655553), and in a family with Parkinson's disease (Dheeraj, 2018). This variant has also been identified in 8/282630 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2018	The FBN1 c.6577G>A; p.Glu2193Lys variant (rs201361628), is reported in the literature in the homozygous state in at least one individual affected with Marfan syndrome (Arnaud 2017), and in the heterozygous state in individuals with vascular anomalies (Mattassi 2018). This variant is reported as uncertain significance/likely benign by multiple laboratories in ClinVar (Variation ID: 255306), and is found in the general population with an overall allele frequency of 0.002% (6/276,956 alleles) in the Genome Aggregation Database. The glutamic acid at codon 2193 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Glu2193Lys variant is uncertain at this time. References: Arnaud P et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet. 2017 Feb;54(2):100-103. Mattassi R et al. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg. 2018 Mar;67(3):922-932.e11. -

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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# 255306; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28655553, 27582083) -

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.37	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.36
Sift	Benign	0.63	T
Sift4G	Benign	0.92	T
Vest4		0.75
MVP		0.74
MPC		0.78
ClinPred		0.18	T
GERP RS		6.2

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: rs201361628; hg19: chr15-48726830; COSMIC: COSV57323942; COSMIC: COSV57323942;