15-48489983-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PP2PP3_ModerateBP6BS2
The NM_000138.5(FBN1):c.2950G>A(p.Val984Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V984V) has been classified as Likely benign.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251474Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727248
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:3
This missense variant replaces valine with isoleucine at codon 984 of the FBN1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with classic Marfan syndrome with cardiovascular manifestations (PMID: 10694921) and in one individual affected with hypertrophic cardiomyopathy (PMID: 23590259). This variant has also been reported in one family, with one individual affected with thoracic aortic aneurysm and dissection; this variant did not segregate with disease and was identified in three unaffected family members (PMID: 27146836). This variant has been identified in 6/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
The p.V984I variant (also known as c.2950G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2950. The valine at codon 984 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with thoracic aortic aneurysm and dissection (Grau U et al. Hum Mutat, 1998;12:137; Poninska JK et al. J Transl Med, 2016 May;14:115). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:2Benign:1
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In silico analysis indicates that this missense variant does not alter protein structure/function; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 10694921, 12203992, 23590259, 12938084, 27146836) -
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Marfan syndrome Uncertain:2
This missense variant replaces valine with isoleucine at codon 984 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with classic Marfan syndrome with cardiovascular manifestations (PMID: 10694921), in an individual affected with thoracic aortic aneurysms and dissections associated with Marfan syndrome (PMID: 27146836), and in an individual affected with hypertrophic cardiomyopathy (PMID: 23590259). This variant was also reported in one case non-obstructive HCM (PMID: 23590259). This variant has been identified in 6/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Uncertain:1
Variant summary: FBN1 c.2950G>A (p.Val984Ile) results in a conservative amino acid change located in the TGF-beta binding (TB) domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2950G>A has been reported in the literature in individuals affected with Marfan Syndrome or hypertrophic cardiomyopathy (e.g. Grau_1998, Fokstuen_2014, Poninska_2016, Collod-Beroud_1997). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9016526, 23590259, 10694921, 27146836). ClinVar contains an entry for this variant (Variation ID: 457184). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Stiff skin syndrome Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Weill-Marchesani syndrome Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Geleophysic dysplasia Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Acromicric dysplasia Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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Ectopia lentis 1, isolated, autosomal dominant Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at