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NM_000138.5(FBN1):c.3410G>A (p.Arg1137His) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 5, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002235656.1

Allele description [Variation Report for NM_000138.5(FBN1):c.3410G>A (p.Arg1137His)]

NM_000138.5(FBN1):c.3410G>A (p.Arg1137His)

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.3410G>A (p.Arg1137His)
HGVS:
  • NC_000015.10:g.48487365C>T
  • NG_008805.2:g.163424G>A
  • NM_000138.5:c.3410G>AMANE SELECT
  • NP_000129.3:p.Arg1137His
  • NP_000129.3:p.Arg1137His
  • LRG_778t1:c.3410G>A
  • LRG_778:g.163424G>A
  • LRG_778p1:p.Arg1137His
  • NC_000015.9:g.48779562C>T
  • NM_000138.4:c.3410G>A
Protein change:
R1137H
Links:
dbSNP: rs137854456
NCBI 1000 Genomes Browser:
rs137854456
Molecular consequence:
  • NM_000138.5:c.3410G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002511396Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Apr 5, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations.

Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, Arnett FC.

Arthritis Rheum. 2001 Apr;44(4):893-901.

PubMed [citation]
PMID:
11315929

Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease.

Li J, Lu C, Wu W, Liu Y, Wang R, Si N, Meng X, Zhang S, Zhang X.

Sci China Life Sci. 2019 Dec;62(12):1630-1637. doi: 10.1007/s11427-018-9491-8. Epub 2019 May 15.

PubMed [citation]
PMID:
31098894

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511396.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: FBN1 c.3410G>A (p.Arg1137His) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251474 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (4e-05 vs 0.00011), allowing no conclusion about variant significance. c.3410G>A has been reported in the literature in cis with another FBN1 variant (p.C2528Y) in an individual affected with Marfan Syndrome (Li_2019). Furthermore, c.3410G>A has been reported in a proband with systemic sclerosis but it was also found in the probands unaffected sibling and daughter (Tan_2001). These reports do 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024