NM_000138.5(FBN1):c.3514G>A (p.Val1172Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000587741.17

Allele description [Variation Report for NM_000138.5(FBN1):c.3514G>A (p.Val1172Met)]

NM_000138.5(FBN1):c.3514G>A (p.Val1172Met)

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.3514G>A (p.Val1172Met)

Other names:

p.V1172M:GTG>ATG

HGVS:

NC_000015.10:g.48487150C>T
NG_008805.2:g.163639G>A
NM_000138.5:c.3514G>AMANE SELECT
NP_000129.3:p.Val1172Met
NP_000129.3:p.Val1172Met
LRG_778t1:c.3514G>A
LRG_778:g.163639G>A
LRG_778p1:p.Val1172Met
NC_000015.9:g.48779347C>T
NM_000138.4:c.3514G>A
c.3514G>A

Protein change:

V1172M

Links:

dbSNP: rs200125037

NCBI 1000 Genomes Browser:

rs200125037

Molecular consequence:

NM_000138.5:c.3514G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000233993	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 9, 2023)	germline	clinical testing	Citation Link,
SCV001473495	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Sep 19, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000233993

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 9, 2023)

germline

clinical testing

Citation Link,

SCV001473495

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Sep 19, 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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000233993.11

#	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 does not alter 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 (Collod-Beroud et al., 2003); Identified in a patient with features of Marfan syndrome in published literature (Lerner-Ellis et al., 2014); however, this individual also harbored a second pathogenic variant in the FBN1 gene but phase was not specified; This variant is associated with the following publications: (PMID: 12938084, 24793577)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473495.1

#	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.3514G>A; p.Val1172Met variant (rs200125037) is reported in the literature in an individual affected with a suspected aortopathy (Lerner-Ellis 2014). However, the affected individual with this variant was also reported to carry a different pathogenic FBN1 variant (Lerner-Ellis 2014). The p.Val1172Met variant is found in the African population with an overall allele frequency of 0.06% (16/24964 alleles) in the Genome Aggregation Database. The valine at codon 1172 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Val1172Met variant is uncertain at this time. References: Lerner-Ellis JP et al. The spectrum of FBN1, TGFÃŸR1, TGFÃŸR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6.

#	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: Mar 11, 2025

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