NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Dec 18, 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:: RCV000586163.25

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)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000233818	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 18, 2024)	germline	clinical testing	Citation Link,
SCV000702389	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Oct 20, 2016)	germline	clinical testing	Citation Link,
SCV003833984	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005435082	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Oct 1, 2024)	germline	clinical testing	Citation Link,
SCV005877206	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain Significance (Oct 7, 2024)	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	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000233818.17

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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)

#	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 Eurofins Ntd Llc (ga), SCV000702389.3

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

From Revvity Omics, Revvity, SCV003833984.2

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

#	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 CeGaT Center for Human Genetics Tuebingen, SCV005435082.2

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

Description

FBN1: PM5, BS1, BS2

#	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		1	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV005877206.1

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

Description

The FBN1 c.4270C>G; p.Pro1424Ala variant (rs201273753) is reported in the literature in individuals with features of Marfan syndrome (Collod-Beroud 1998, Comeglio 2001, Groth 2016), but has also been reported in an unaffected carrier (Howarth 2007) and in individuals without a related cardiovascular phenotype (Damrauer 2019). Additionally, this variant was reported to be compound heterozygous with a pathogenic FBN1 variant (p.Arg2680Cys) in a family member who did not have an aggravated phenotype compared to another member only carrying the pathogenic p.Arg2680Cys variant (Arnaud 2017). At ARUP Laboratories we have also detected the p.Pro1424Ala variant in an individual who also carried a pathogenic frameshift FBN1 variant but phase of the variants was not determined. The p.Pro1424Ala variant is reported in ClinVar (Variation ID: 42355). It is observed in the general population with an overall allele frequency of 0.02% (57/282832 alleles) in the Genome Aggregation Database which is higher than expected for this disorder. Computational analyses predict that this variant is deleterious (REVEL: 0.754). Based on currently available information, the clinical significance of the p.Pro1424Ala variant is uncertain at this time. References: Arnaud P et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet. 2017 Feb;54(2):100-103. PMID: 27582083. Collod-Beroud G et al. Marfan Database (third edition): new mutations and new routines for the software. Nucleic Acids Res. 1998 Jan 1;26(1):229-3. PMID: 9399842. Comeglio P et al. Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome. Hum Mutat. 2001 Sep;18(3):251. PMID: 11524736. Damrauer SM et al. FBN1 Coding Variants and Nonsyndromic Aortic Disease. Circ Genom Precis Med. 2019 Jun;12(6):e002454. PMID: 31211626. Groth KA et al. Difficulties in diagnosing Marfan syndrome using current FBN1 databases. Genet Med. 2016 Jan;18(1):98-102. PMID: 25812041. Howarth R et al. Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test. 2007 Summer;11(2):146-52. PMID: 17627385.

#	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 13, 2025

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