NM_000138.5(FBN1):c.1036T>C (p.Ser346Pro) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 2, 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:: RCV000154494.5

Allele description [Variation Report for NM_000138.5(FBN1):c.1036T>C (p.Ser346Pro)]

NM_000138.5(FBN1):c.1036T>C (p.Ser346Pro)

Genes:

LOC113939944:Sharpr-MPRA regulatory region 9539 [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.1036T>C (p.Ser346Pro)

HGVS:

NC_000015.10:g.48520770A>G
NG_008805.2:g.130019T>C
NG_063729.1:g.339A>G
NM_000138.5:c.1036T>CMANE SELECT
NP_000129.3:p.Ser346Pro
NP_000129.3:p.Ser346Pro
LRG_778t1:c.1036T>C
LRG_778:g.130019T>C
LRG_778p1:p.Ser346Pro
NC_000015.9:g.48812967A>G
NM_000138.4:c.1036T>C

Protein change:

S346P

Links:

dbSNP: rs727504361

NCBI 1000 Genomes Browser:

rs727504361

Molecular consequence:

NM_000138.5:c.1036T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204164	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004030039	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24793577, 25101912 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204164

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 15, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004030039

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD).

Lerner-Ellis JP, Aldubayan SH, Hernandez AL, Kelly MA, Stuenkel AJ, Walsh J, Joshi VA.

Mol Genet Metab. 2014 Jun;112(2):171-6. doi: 10.1016/j.ymgme.2014.03.011. Epub 2014 Apr 2.

PubMed [citation]

PMID:: 24793577

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204164.4

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

Description

proposed classification - variant undergoing re-assessment, contact laboratory

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004030039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: FBN1 c.1036T>C (p.Ser346Pro) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1036T>C has been reported in the literature in an individual diagnosed with Thoracic Aortic Aneurysms and Dissections, however, authors classified the variant as VUS (example: Lerner-Ellis_2014). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. 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: 24793577, 25101912). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Sep 29, 2024

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