NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala) AND Familial thoracic aortic aneurysm and aortic dissection

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 28, 2023
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:: RCV000771903.18

Allele description

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:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000317386	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely benign (May 25, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11748851, 14695540, 17657824, 19161152, 19293843, 25637381, 26621581, 28655553, 9399842 Citation Link,
SCV000904667	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 28, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9399842, 11748851, 14695540, 17627385, 17657824, 19293843, 23506379, 25812041, 26621581, 27582083, 25741868
SCV001279912	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jun 17, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000317386

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely benign
(May 25, 2018)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000904667

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 28, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001279912

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jun 17, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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, Emery H, Collins AL, Howarth RJ, Yearwood CM, Cross E, Duncan PJ, Bunyan DJ, Harvey JF, Foulds NC.

Am J Med Genet A. 2009 Feb;149A(2):161-70. doi: 10.1002/ajmg.a.32593.

PubMed [citation]

PMID:: 19161152

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000317386.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

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.

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

From Color Diagnostics, LLC DBA Color Health, SCV000904667.4

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

From Illumina Laboratory Services, Illumina, SCV001279912.1

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

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). 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.

#	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

Last Updated: Apr 20, 2024

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