rs397515823

Variant names:

• chr15-48452595-C-A
• rs397515823
• NM_000138.5:c.5512G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48452595-C-A
• chr15-48452595-C-G
• chr15-48452595-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.5512G>T​(p.Gly1838Cys) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1838S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.83
• Publications: 5 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 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48452595-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457232.
• 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 Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 15-48452595-C-A is Pathogenic according to our data. Variant chr15-48452595-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 42386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.5512G>T	p.Gly1838Cys	missense	Exon 45 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.5512G>T	p.Gly1838Cys	missense	Exon 44 of 65	NP_001393645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.5512G>T	p.Gly1838Cys	missense	Exon 45 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.5512G>T		non_coding_transcript_exon	Exon 45 of 67	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.*1275G>T		non_coding_transcript_exon	Exon 20 of 31	ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Sep 26, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly1838Cys variant in FBN1 has been identified in 3 individuals with clini cal features of Marfan syndrome (Ganesh 2006, Beatens 2011, LMM data) and was ab sent from large population studies. Computational prediction tools and conservat ion analysis suggest that the p.Gly1838Cys variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In addit ion, one study observed abnormal fibril patterns using firbilin-1 staining in ti ssue from an individual who carried this variant (Ganesh 2006). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Gly1838Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2 ; PS4_Moderate; PP3; PS3_Supporting (Richards 2015).

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS5, PP4

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Dec 22, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

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: The FBN1 c.5512G>T (p.Gly1838Cys) variant causes a missense change involving a conserved nucleotide with 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predicting a "deleterious" outcome, although these predictions have yet to be functionally assessed. However, this missense mutation involved a highly conserved Gly residue, replacing it with a Cys. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage . In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, a missense change to a cysteine residue could disrupt normal disulfide binding, effecting secondary or tertiary structure, or possibly impairing fibrillin interactions. In addition, the variant of interest was absent in 121354 control chromosomes, has been reported in affected individuals via publications, and one clinical lab has classified the variant as pathogenic. Therefore, taking all available lines of evidence, the variant of interest is classified as Likely Pathogenic until additional information becomes available.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
MutPred		0.95		Gain of catalytic residue at P1837 (P = 0.0074)
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs397515823; hg19: chr15-48744792; COSMIC: COSV57311953;