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Variant: NM_000138.4(FBN1):c.629G>A (p.Cys210Tyr)

CA392446003

426140 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 77b48e1f-cb71-4c80-a685-6379cde2503d

HGVS expressions

NM_000138.4:c.629G>A
NM_000138.4(FBN1):c.629G>A (p.Cys210Tyr)
NC_000015.10:g.48537718C>T
CM000677.2:g.48537718C>T
NC_000015.9:g.48829915C>T
CM000677.1:g.48829915C>T
NC_000015.8:g.46617207C>T
NG_008805.2:g.113071G>A
ENST00000316623.10:c.629G>A
ENST00000316623.9:c.629G>A
ENST00000537463.6:c.629G>A
NM_000138.5:c.629G>A
NM_000138.5(FBN1):c.629G>A (p.Cys210Tyr)

Likely Pathogenic

Met criteria codes 5
PM2 PM1 PS4_Moderate PP3 PP2
Not Met criteria codes 13
PM6 PM5 BA1 BS4 BS3 BS1 BP5 BP2 BP4 PS2 PS3 PP4 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
The NM_00138 c.629G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 210 (p.Cys210Tyr). This variant was reported in an individual diagnosed with Marfan syndrome (PMID 33711475), and in an individual with ectopia lentis, pectus carinatum, foot deformity, dural ectasia, and protrusio acetabuli (PMID 31825148) (PS4_Mod). This variant was also found in a 7-year-old male proband with lens luxation, big stature, but a normal cardiac ultrasound, and was inherited from his healthy father, however ophthalmology exams are pending (Internal data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/). The variant in FBN1 has been reported twice in ClinVar as likely pathogenic (Variation ID: 426140). This variant affects a cysteine residue is in the 1st Hybrid domain of protein (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.94) (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: PM1, PS4_Moderate, PM2_Supportive, PP2, PP3
Met criteria codes
PM2
Absent in the Genome Aggregation Database (gnomAD).
PM1
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation: Cys in the 1st Hybid domain.
PS4_Moderate
Reported in 2 individuals with MFS, and in one individual with features of MFS= 2.5 pts
PP3
REVEL score 0.94; >0.75 threshold
PP2
Based on the SVI WG recommendation concerning constraint scores: if missense constraint z scores are > 3.09 in ExAC, this criterion may be used. For FBN1, the constraint score is higher than 5. Hence, PP2 is applicable as described.
Not Met criteria codes
PM6
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
BA1
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
BP5
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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
PP4
No clinical information available.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-06-15
Published on: 2023-06-15
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