chr15-48463123-G-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.5183C>T(p.Ala1728Val) 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. 11/18 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. A1728T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21683322, 27245183, 34006472, 33082559, 36998968) -
FBN1: PM2, PM6, PS4:Moderate, PP1, PP2, PP3, PP4 -
Metaphyseal chondrodysplasia Pathogenic:1
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Geleophysic dysplasia 2 Pathogenic:1
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Geleophysic dysplasia Pathogenic:1
The FBN1 c.5183C>T (p.Ala1728Val) missense variant has been reported in two studies and found in a total of four individuals from three unrelated families affected with FBN1-related disorders, including acromicric dysplasia and geleophysic dysplasia, all in a heterozygous state (Le Goff et al. 2011; de Bruin et al. 2016). The individual reported in Le Goff et al. (2011) study was de novo for the variant, while one patient reported in de Bruin et al. (2016) study inherited the variant from affected mother. The variant was absent from the 1000 Genomes Project, Exome Sequencing Project, the Exome Aggregation Consortium and the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.Ala1728Val is classified as likely pathogenic for FBN1-related disorders. This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. -
Acromicric dysplasia Pathogenic:1
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Wide mouth;C0349588:Short stature;C1849075:Relative macrocephaly;C1849367:Wide nasal bridge Pathogenic:1
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FBN1-related disorder Pathogenic:1
The FBN1 c.5183C>T variant is predicted to result in the amino acid substitution p.Ala1728Val. This variant has been reported in multiple individuals with geleophysic dysplasia (Table 2, de novo, Le Goff et al. 2011. PubMed ID: 21683322; Table S2, Fan et al. 2021. PubMed ID: 34006472). This variant has also been reported in multiple individuals with acromicric dysplasia (Figure 1, de Bruin et al. 2016. PubMed ID: 27245183; Table S3, Marzin et al. 2020. PubMed ID: 33082559; Figure 1, Shen et al. 2023. PubMed ID: 36998968). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1728 of the FBN1 protein (p.Ala1728Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of acromicric dysplasia or geleophysic dysplasia (PMID: 21683322, 27245183). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430150). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala1728 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21683322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Connective tissue disorder Pathogenic:1
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Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
PM2_Supporting+PS4_Moderate+PM6+PP2+PP3+PP4+PM5 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at