rs61746008
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000138.5(FBN1):c.8176C>T(p.Arg2726Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00071 in 152166 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2726Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
Links
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.8176C>T | p.Arg2726Trp | missense_variant | 65/66 | ENST00000316623.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.8176C>T | p.Arg2726Trp | missense_variant | 65/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000710 AC: 108AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000728 AC: 183AN: 251466Hom.: 1 AF XY: 0.000751 AC XY: 102AN XY: 135906
GnomAD4 exome AF: 0.000761 AC: 1113AN: 1461880Hom.: 2 AF XY: 0.000758 AC XY: 551AN XY: 727240
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:4Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of DISEASE. (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg2726Leu) and p.(Arg2726Gln) have been reported VUS in ClinVar, but p.(Arg2726Gln) has also been regarded likely benign (PMID: 31227806). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported both as VUS and likely benign in ClinVar and it used to be known as a Marfanoid Skeletal Syndrome variant, as it has mostly been detected in individuals without cardiac and ocular manifestations (OMIM). More recently, even though some consider it causative with incomplete penetrance (PMID: 26875674), others see it as a likely benign variant (PMID: 31227806). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies have shown that it affects the conversion mediated of profibrillin to fibrillin (PMIDs: 26875674, 7738200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Dec 01, 2015 | - - |
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as causing Marfanoid-like features. It has been found 13 times in our laboratory, always inherited when parents are tested, and not always in patients with Marfanoid features. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 19, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | Criteria applied: BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | See Variant Classification Assertion Criteria. - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2016 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2023 | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 25, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 20, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2019 | Variant summary: FBN1 c.8176C>T (p.Arg2726Trp) results in a non-conservative amino acid change in 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 0.00072 in 252730 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.8176C>T has been reported in the literature in individuals affected with Marfan Syndrome, as well as in mildly affected and unaffected family members, suggesting incomplete penetrance, or a mostly benign nature. Since the penetrance of Marfan Syndrome (0.71) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Co-occurrences with other pathogenic FBN1 variants have been reported (e.g. Stheneur 2009: c.3299G>T (p.Gly1100V), c.6388G>A (p.Glu2130Lys), c.1416C>A (p.Cys472X); Arnaud 2017: c.1585C>T (Arg529X), c.6388G>A (p.Glu2130Lys); Becerra-Munoz 2018: c.7754T>C, (p.Ile2585Thr); and in an internal sample: c.3073_3074insA (p.Phe1025fsX7)), providing supporting evidence for a benign role. Some publications also reported experimental evidence evaluating an impact on protein function, showing a decreased protein processing (C-terminal propeptide cleavage) (Milewicz 1995, Lonnqvist 1998). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, PreventionGenetics | - | - - |
Stiff skin syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | - - |
Ectopia lentis 1, isolated, autosomal dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 2018 | 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