Variant: NM_000138.5(FBN1):c.1030C>T (p.Arg344Cys)

CA043398

548999 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 96b94f7f-0205-4ee2-a1ff-0159f3efcc0e

Approved on: 2023-11-16

Published on: 2023-11-16

HGVS expressions

NM_000138.5:c.1030C>T
NM_000138.5(FBN1):c.1030C>T (p.Arg344Cys)
NC_000015.10:g.48520776G>A
CM000677.2:g.48520776G>A
NC_000015.9:g.48812973G>A
CM000677.1:g.48812973G>A
NC_000015.8:g.46600265G>A
NG_008805.2:g.130013C>T
ENST00000316623.10:c.1030C>T
ENST00000316623.9:c.1030C>T
ENST00000537463.6:c.636+16935C>T
NM_000138.4:c.1030C>T

Likely Pathogenic

• Met criteria codes: PP3 PP2 PM1 PS4_Moderate

• Not Met criteria codes: PS2 PS1 PS3 PP1 PP4 PM3 PM5 PM4 PM6 PVS1 PM2 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Expert Panel

FBN1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

FBN1 VCEP

NM_00138 c.1030C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 344 (p.Arg344Cys). This variant was found in one published proband with unspecified ocular and skeletal features, one internal proband with ectopia lentis and a systemic score of 3, and two probands with isolated thoracic aortic aneurysm and dissection, none of whom met the revised Ghent criteria for Marfan syndrome (PS4_moderate; PMID: 25652356; UZG & Invitae internal data, ClinVar Variation ID: 548999). This variant is present in gnomAD v2.1.1 (3/113642 [0.0026%] European alleles; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact protein structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_moderate, PM1, PP2, PP3.

Met criteria codes

• PP3: REVEL = 0.884
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: cysteine-creating variant
• PS4_Moderate: 4 probands worth a total 2.5 PS4 points

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: proband from UZ Gent accounted for in PS4 criterion
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: highest MAF: 3/113642 alleles (0.0026%) in gnomAD v2.1.1
• BA1: highest MAF: 3/113642 alleles (0.0026%) in gnomAD v2.1.1
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: highest MAF: 3/113642 alleles (0.0026%) in gnomAD v2.1.1
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline