Submissions for variant NM_000138.5(FBN1):c.79G>A (p.Ala27Thr)

gnomAD frequency: 0.00019  dbSNP: rs25397

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000358510	SCV004037322	benign	Marfan syndrome	2023-09-28	reviewed by expert panel	curation	The NM_000138.5 c.79G>A, is a missense variant in FBN1 predicted to cause a substitution of a alanine acid by threonine at amino acid 27 (p.Ala27Thr). This variant has been previously reported in ClinVar as likely benign and benign (Variation ID: 163486). This variant has been identified in 129/19954 (0.65%) of individuals of East Asian origin (MAF: 0.65%) (BA1; https://gnomad.broadinstitute.org/ version 2.1.1). It has been reported in individuals with thoracic aortic aneurysm and/or dissection, and in individuals with clinical features of Marfan syndrome, however it was considered to be a polymorphism (PMID 26272055, 19839986, 16835936). Computational prediction tools and conservation analysis suggests no impact on the protein (REVEL: 0.097) (BP4). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two 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 ClinGenFBN1 VCEP: BA1, BP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150707	SCV000198115	likely benign	not specified	2015-10-12	criteria provided, single submitter	clinical testing	p.Ala27Thr in exon 1 of FBN1: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (52/8652) of East Asian chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs25397).
GeneDx	RCV000588579	SCV000233706	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26272055, 19839986, 16835936)
Ambry Genetics	RCV000246481	SCV000318993	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-09-16	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000246481	SCV000392730	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000338830	SCV000392731	benign	Stiff skin syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000391023	SCV000392732	benign	Acromicric dysplasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000303596	SCV000392733	benign	Geleophysic dysplasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000358510	SCV000392734	benign	Marfan syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000391019	SCV000392735	benign	Weill-Marchesani syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000363432	SCV000392737	benign	Ectopia lentis 1, isolated, autosomal dominant	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001084497	SCV000557027	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588579	SCV000695613	benign	not provided	2017-07-20	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.79G>A (p.Ala27Thr) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 60/124386 control chromosomes, predominantly observed in the East Asian cohort at a frequency of 0.00601 (52/8652). This frequency is about 53 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000246481	SCV000904489	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-14	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588579	SCV001798110	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588579	SCV001808335	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588579	SCV001964661	likely benign	not provided		no assertion criteria provided	clinical testing