Variant: NM_000138.4(FBN1):c.8363C>T (p.Thr2788Met)

CA059963

263832 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: a1d82f83-e29b-4022-a4ae-7d95a9d27888

Approved on: 2023-02-01

Published on: 2023-02-01

HGVS expressions

NM_000138.4:c.8363C>T
NM_000138.4(FBN1):c.8363C>T (p.Thr2788Met)
NC_000015.10:g.48411243G>A
CM000677.2:g.48411243G>A
NC_000015.9:g.48703440G>A
CM000677.1:g.48703440G>A
NC_000015.8:g.46490732G>A
NG_008805.2:g.239546C>T
ENST00000682158.1:n.1744C>T
ENST00000682170.1:n.2544C>T
ENST00000682767.1:n.1660C>T
ENST00000316623.10:c.8363C>T
ENST00000674301.1:n.3529C>T
ENST00000316623.9:c.8363C>T
ENST00000559133.5:n.3732C>T
ENST00000561429.1:n.618C>T
NM_000138.5:c.8363C>T
NM_000138.5(FBN1):c.8363C>T (p.Thr2788Met)

Benign

• Met criteria codes: BA1

• Not Met criteria codes: PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1

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

The NM_00138 c.8363C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by methionine at amino acid 2788 (p.Thr2788Met). The variant in FBN1 has been reported 13 times in ClinVar: 12 times as likely benign and once as benign (Variation ID: 263832). This variant has been identified in 44 individuals of African origin (gnomAD version 3.1.1, MAF: 0.1%, one homozygous) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.356). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1.

Met criteria codes

• BA1: gnomAD v3.1,1 African/ African American frequency: 0.1% (44/41400) gnomAD v2.1.1: African/ African American frequency: 0.096% (24/24968)

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Variant meets BS1, therefore although found in several probands with suspicion of MFS or TAD, this criterium cannot be used
• PS3: 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
• PP4: 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
• PP3: REVEL score: 0.356
• PP2: Due to the presence of benign arguments, PP2 cannot be applied.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: Missense variant
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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: 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: Missense variant
• BP4: REVEL score: 0.356
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: Missense variant
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline