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

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Feb 5, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000035194.21

Allele description [Variation Report for NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)]

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

Genes:

LOC126862124:CDK7 strongly-dependent group 2 enhancer GRCh37_chr15:48764566-48765765 [Gene]
FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

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

Other names:

p.P1424A:CCA>GCA

HGVS:

NC_000015.10:g.48472617G>C
NG_008805.2:g.178172C>G
NM_000138.5:c.4270C>GMANE SELECT
NP_000129.3:p.Pro1424Ala
NP_000129.3:p.Pro1424Ala
LRG_778t1:c.4270C>G
LRG_778:g.178172C>G
LRG_778p1:p.Pro1424Ala
NC_000015.9:g.48764814G>C
NM_000138.4:c.4270C>G
c.4270C>G

Protein change:

P1424A

Links:

dbSNP: rs201273753

NCBI 1000 Genomes Browser:

rs201273753

Molecular consequence:

NM_000138.5:c.4270C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190205	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000678218	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000787041	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Uncertain significance (Nov 7, 2017)	germline	clinical testing
SCV001139604	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001279911	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jun 17, 2019)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 17627385, 14695540, 11524736, 17657824, 26621581, 25812041, 27582083, 9399842, 24941995, 19161152, 19293843 Citation Link,
SCV004814746	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9399842, 11748851, 14695540, 17627385, 17657824, 19293843, 23506379, 25812041, 26621581, 27582083, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	63	3	not provided	108544	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.

Comeglio P, Evans AL, Brice GW, Child AH.

Hum Mutat. 2001 Sep;18(3):251. Corrected and republished in: Hum Mutat. 2001 Dec;18(6):546-7. doi: 10.1002/humu.1235.

PubMed [citation]

PMID:: 11524736

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.

Yang RQ, Jabbari J, Cheng XS, Jabbari R, Nielsen JB, Risgaard B, Chen X, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS, Tfelt-Hansen J.

BMC Genet. 2014 Jun 18;15:74. doi: 10.1186/1471-2156-15-74.

PubMed [citation]

PMID:: 24941995
PMCID:: PMC4070351

See all PubMed Citations (14)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190205.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000678218.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	3	not provided

From Center for Medical Genetics Ghent, University of Ghent, SCV000787041.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001139604.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001279911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004814746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	63	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		63	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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