VCV000042355.38 - ClinVar

NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(23)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(11); Benign(6); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

Variation ID: 42355 Accession: VCV000042355.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 48472617 (GRCh38) [ NCBI UCSC ] 15: 48764814 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2014	Sep 16, 2024	May 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000138.5:c.4270C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000129.3:p.Pro1424Ala	missense
NC_000015.10:g.48472617G>C
NC_000015.9:g.48764814G>C
NG_008805.2:g.178172C>G
LRG_778:g.178172C>G
LRG_778t1:c.4270C>G	LRG_778p1:p.Pro1424Ala

... more HGVS ... less HGVS

Protein change

P1424A

Other names

p.P1424A:CCA>GCA

Canonical SPDI

NC_000015.10:48472616:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00059

Exome Aggregation Consortium (ExAC) 0.00018

The Genome Aggregation Database (gnomAD), exomes 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

The Genome Aggregation Database (gnomAD) 0.00034

Links

ClinGen: CA014918 dbSNP: rs201273753 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FBN1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7580	7914
LOC126862124	-	-	-	GRCh38	-	131

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Marfan syndrome	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Feb 5, 2024	RCV000035194.21
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 15, 2023	RCV000161118.18
Familial thoracic aortic aneurysm and aortic dissection Marfan syndrome	Likely benign (1)	criteria provided, single submitter	Jan 30, 2024	RCV000226865.18
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 14, 2024	RCV000586163.19
Acute aortic dissection Congenital aneurysm of ascending aorta	Uncertain significance (1)	no assertion criteria provided	Jan 20, 2016	RCV000755199.8
Familial thoracic aortic aneurysm and aortic dissection	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 28, 2023	RCV000771903.19
Acromicric dysplasia Ectopia lentis 1, isolated, autosomal dominant Geleophysic dysplasia 2 MASS syndrome Marfan syndrome Progeroid and marfanoid aspect-lipodystrophy syndrome Stiff skin syndrome Weill-Marchesani syndrome 2, dominant	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 25, 2022	RCV000765222.10
Weill-Marchesani syndrome	Benign (1)	criteria provided, single submitter	Jun 17, 2019	RCV001116398.11
Stiff skin syndrome	Benign (1)	criteria provided, single submitter	Jun 17, 2019	RCV001121321.11
Geleophysic dysplasia	Benign (1)	criteria provided, single submitter	Jun 17, 2019	RCV001121322.11
Acromicric dysplasia	Benign (1)	criteria provided, single submitter	Jun 17, 2019	RCV001121323.11
Ectopia lentis 1, isolated, autosomal dominant	Benign (1)	criteria provided, single submitter	Jun 17, 2019	RCV001121324.11
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Weill-Marchesani syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001274466.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Stiff skin syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279907.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Geleophysic dysplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279908.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Likely benign (May 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695537.2 First in ClinVar: Mar 17, 2018 Last updated: Jun 24, 2023	Publications: PubMed (14) PubMed: 11748851‚ 14695540‚ 12938084‚ 17657824‚ 17627385‚ 19161152‚ 9399842‚ 19293843‚ 23506379‚ 24941995‚ 25637381‚ 26621581‚ 27153395‚ 26787436 Comment: Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of … (more) Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251532 control chromosomes. The observed variant frequency is approximately 1.8 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 benign. c.4270C>G has been reported in the literature in individuals affected with features of or undergoing testing for Marfan Syndrome/familial thoracic aortic aneurysms and dissections. 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: 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 27153395, 26787436). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=11, B/LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acromicric dysplasia Ectopia lentis 1, isolated, autosomal dominant Marfan syndrome Stiff skin syndrome MASS syndrome Weill-Marchesani syndrome 2, dominant Geleophysic dysplasia 2 Progeroid and marfanoid aspect-lipodystrophy syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896458.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Oct 21, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058836.5 First in ClinVar: May 03, 2013 Last updated: Oct 09, 2016	Publications: PubMed (4) PubMed: 11524736‚ 9399842‚ 14695540‚ 16222657 Comment: The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud … (more) The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant . (less) Number of individuals with the variant: 2
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Marfan syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139604.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Benign (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Acromicric dysplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279909.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Uncertain significance (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Marfan syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279911.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (11) PubMed: 17627385‚ 14695540‚ 11524736‚ 17657824‚ 26621581‚ 25812041‚ 27582083‚ 9399842‚ 24941995‚ 19161152‚ 19293843 Comment: 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, … (more) 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. (less)
Benign (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ectopia lentis 1, isolated, autosomal dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279910.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Uncertain significance (Jun 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279912.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Mar 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003833984.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Feb 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000904667.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 9399842‚ 11748851‚ 14695540‚ 17627385‚ 17657824‚ 19293843‚ 23506379‚ 25812041‚ 26621581‚ 27582083 Comment: This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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. (less)
Uncertain Significance (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Marfan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004814746.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (10) PubMed: 9399842‚ 11748851‚ 14695540‚ 17627385‚ 17657824‚ 19293843‚ 23506379‚ 25812041‚ 26621581‚ 27582083 Comment: This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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. (less) Number of individuals with the variant: 63
Uncertain significance (Oct 20, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000702389.2 First in ClinVar: Oct 09, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FBN1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jan 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Geleophysic dysplasia 2 Weill-Marchesani syndrome 2, dominant Ectopia lentis 1, isolated, autosomal dominant MASS syndrome Progeroid and marfanoid aspect-lipodystrophy syndrome Acromicric dysplasia Marfan syndrome Stiff skin syndrome Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003919944.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: This variant has been reported in the literature in at least 11 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom … (more) This variant has been reported in the literature in at least 11 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom were reported as compound heterozygotes (Collod-Beroud 1998 PMID:9399842, Comeglio 2001 PMID:11748851, Biggin 2004 PMID:14695540, Comeglio 2007 PMID:17657824, Howarth 2007 PMID:17627385, Stheneur 2009 PMID:19293843, Turner 2009 PMID:19161152, Callier 2013 PMID:23506379, Arnaud 2017 PMID:27582083, Mattessi 2018 PMID:28655553). This variant is present in 0.2% (31/15280) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3). Of note, the frequency of this variant is inconsistent with the expected incidence of this condition and several entries in ClinVar have noted this information in their classification (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. A Likely Pathogenic variant at the same amino acid position (p.Pro1424Ser) has been previously reported (Arbustini 2005 PMID:16222657; Piqueras-Flores 2019 PMID:31053375). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Benign (Mar 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Marfan syndrome Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000678218.2 First in ClinVar: Feb 24, 2015 Last updated: Dec 02, 2023	Comment: This variant has been reported in the literature in several individuals with a clinical suspicion or diagnosis of Marfan syndrome (Selected publications: Comeglio 2001 PMID: … (more) This variant has been reported in the literature in several individuals with a clinical suspicion or diagnosis of Marfan syndrome (Selected publications: Comeglio 2001 PMID: 11748851, Comeglio 2007 PMID: 17657824, Stheneur 2009 PMID: 19293843, Arnaud 2017 PMID: 27582083). This variant is present in gnomAD (Highest reported MAF: 0.2% [31/15280]; https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3) and in ClinVar (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, a different variant at the same amino acid position (p.Pro1424Ser) has been previously reported in association with disease (Arbustini 2005 PMID: 16222657; Piqueras-Flores 2019 PMID: 31053375). However, because of this variant's high frequency in the general population, this variant is classified as benign. (less)
Likely benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Marfan syndrome Familial thoracic aortic aneurysm and aortic dissection Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283627.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (May 25, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000317386.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 11748851‚ 14695540‚ 17657824‚ 19161152‚ 19293843‚ 25637381‚ 26621581‚ 28655553‚ 9399842 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. (less)
Uncertain significance (May 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233818.16 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding 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: 9399842, 25812041, 25637381, 28655553, 14695540, 19161152, 19293843, 23506379, 24941995, 25944730, 27647783, 27582083, 27153395, 31098894, 12938084, 17657824, 31211626, 16222657, 11524736, 26787436, 11748851, 26621581, 17627385) (less)
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Marfan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190205.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Uncertain significance (Nov 07, 2017)	no assertion criteria provided Method: clinical testing	Marfan syndrome Affected status: yes Allele origin: germline	Center for Medical Genetics Ghent, University of Ghent Accession: SCV000787041.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018
Uncertain significance (Jan 20, 2016)	no assertion criteria provided Method: research	Familial thoracic aortic aneurysms Acute aortic dissections Affected status: yes Allele origin: unknown	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000883028.1 First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019	Publications: PubMed (1) PubMed: 26621581
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Comment:

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251532 control chromosomes. The observed variant frequency is approximately 1.8 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 benign. c.4270C>G has been reported in the literature in individuals affected with features of or undergoing testing for Marfan Syndrome/familial thoracic aortic aneurysms and dissections. 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: 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 27153395, 26787436). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=11, B/LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant .

Comment:

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.

Comment:

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.

Comment:

This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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.

Comment:

This variant has been reported in the literature in at least 11 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom were reported as compound heterozygotes (Collod-Beroud 1998 PMID:9399842, Comeglio 2001 PMID:11748851, Biggin 2004 PMID:14695540, Comeglio 2007 PMID:17657824, Howarth 2007 PMID:17627385, Stheneur 2009 PMID:19293843, Turner 2009 PMID:19161152, Callier 2013 PMID:23506379, Arnaud 2017 PMID:27582083, Mattessi 2018 PMID:28655553). This variant is present in 0.2% (31/15280) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3). Of note, the frequency of this variant is inconsistent with the expected incidence of this condition and several entries in ClinVar have noted this information in their classification (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. A Likely Pathogenic variant at the same amino acid position (p.Pro1424Ser) has been previously reported (Arbustini 2005 PMID:16222657; Piqueras-Flores 2019 PMID:31053375). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

This variant has been reported in the literature in several individuals with a clinical suspicion or diagnosis of Marfan syndrome (Selected publications: Comeglio 2001 PMID: 11748851, Comeglio 2007 PMID: 17657824, Stheneur 2009 PMID: 19293843, Arnaud 2017 PMID: 27582083). This variant is present in gnomAD (Highest reported MAF: 0.2% [31/15280]; https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3) and in ClinVar (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, a different variant at the same amino acid position (p.Pro1424Ser) has been previously reported in association with disease (Arbustini 2005 PMID: 16222657; Piqueras-Flores 2019 PMID: 31053375). However, because of this variant's high frequency in the general population, this variant is classified as benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding 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: 9399842, 25812041, 25637381, 28655553, 14695540, 19161152, 19293843, 23506379, 24941995, 25944730, 27647783, 27582083, 27153395, 31098894, 12938084, 17657824, 31211626, 16222657, 11524736, 26787436, 11748851, 26621581, 17627385)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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.

Comment:

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.	Mattassi R	Journal of vascular surgery	2018	PMID: 28655553
Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.	Arnaud P	Journal of medical genetics	2017	PMID: 27582083
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Genotype impacts survival in Marfan syndrome.	Franken R	European heart journal	2016	PMID: 26787436
Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.	Regalado ES	Clinical genetics	2016	PMID: 26621581
Difficulties in diagnosing Marfan syndrome using current FBN1 databases.	Groth KA	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 25812041
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.	Yang RQ	BMC genetics	2014	PMID: 24941995
Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.	Callier P	Clinical genetics	2013	PMID: 23506379
Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene.	Stheneur C	European journal of human genetics : EJHG	2009	PMID: 19293843
Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy.	Turner CL	American journal of medical genetics. Part A	2009	PMID: 19161152
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.	Comeglio P	Human mutation	2007	PMID: 17657824
Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory.	Howarth R	Genetic testing	2007	PMID: 17627385
Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.	Arbustini E	Human mutation	2005	PMID: 16222657
Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy.	Biggin A	Human mutation	2004	PMID: 14695540
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database.	Collod-Béroud G	Human mutation	2003	PMID: 12938084
Erratum: Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.	Comeglio P	Human mutation	2001	PMID: 11748851
Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.	Comeglio P	Human mutation	2001	PMID: 11524736
Marfan Database (third edition): new mutations and new routines for the software.	Collod-Béroud G	Nucleic acids research	1998	PMID: 9399842
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FBN1	-	-	-	-
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Text-mined citations for rs201273753 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201273753 ...