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NM_212482.4(FN1):c.367T>C (p.Cys123Arg) AND Spondylometaphyseal dysplasia - Sutcliffe type

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Oct 15, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_212482.4(FN1):c.367T>C (p.Cys123Arg)]

NM_212482.4(FN1):c.367T>C (p.Cys123Arg)

FN1:fibronectin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_212482.4(FN1):c.367T>C (p.Cys123Arg)
  • NC_000002.12:g.215433372A>G
  • NG_012196.1:g.7697T>C
  • NM_001306129.2:c.367T>C
  • NM_001306130.2:c.367T>C
  • NM_001306131.2:c.367T>C
  • NM_001306132.2:c.367T>C
  • NM_001365517.2:c.367T>C
  • NM_001365518.2:c.367T>C
  • NM_001365519.2:c.367T>C
  • NM_001365520.2:c.367T>C
  • NM_001365521.2:c.367T>C
  • NM_001365522.2:c.367T>C
  • NM_001365523.2:c.367T>C
  • NM_001365524.2:c.367T>C
  • NM_002026.4:c.367T>C
  • NM_054034.3:c.367T>C
  • NM_212474.3:c.367T>C
  • NM_212476.3:c.367T>C
  • NM_212478.3:c.367T>C
  • NM_212482.4:c.367T>CMANE SELECT
  • NP_001293058.2:p.Cys123Arg
  • NP_001293059.2:p.Cys123Arg
  • NP_001293060.2:p.Cys123Arg
  • NP_001293061.2:p.Cys123Arg
  • NP_001352446.1:p.Cys123Arg
  • NP_001352447.1:p.Cys123Arg
  • NP_001352448.1:p.Cys123Arg
  • NP_001352449.1:p.Cys123Arg
  • NP_001352450.1:p.Cys123Arg
  • NP_001352451.1:p.Cys123Arg
  • NP_001352452.1:p.Cys123Arg
  • NP_001352453.1:p.Cys123Arg
  • NP_002017.2:p.Cys123Arg
  • NP_473375.2:p.Cys123Arg
  • NP_997639.2:p.Cys123Arg
  • NP_997641.2:p.Cys123Arg
  • NP_997643.2:p.Cys123Arg
  • NP_997647.2:p.Cys123Arg
  • NC_000002.11:g.216298095A>G
  • NC_000002.11:g.216298095A>G
  • NM_212482.2:c.367T>C
Protein change:
C123R; CYS123ARG
OMIM: 135600.0006; dbSNP: rs1553667072
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001306129.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306130.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306131.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306132.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365517.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365518.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365519.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365520.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365521.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365522.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365523.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365524.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002026.4:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_054034.3:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212474.3:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212476.3:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212478.3:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212482.4:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]


Spondylometaphyseal dysplasia - Sutcliffe type
Sutcliffe type of spondylometaphyseal dysplasia; Sutcliffe SMD; Spondylometaphyseal dysplasia, 'corner fracture' type
MONDO: MONDO:0008479; MedGen: C0432221; Orphanet: 93315; OMIM: 184255

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
no assertion criteria provided
(Dec 28, 2017)
germlineliterature only

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

SCV000883266SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 15, 2018)
de novocuration

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novounknownnot providednot providednot providednot providednot providedcuration
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".

Lee CS, Fu H, Baratang N, Rousseau J, Kumra H, Sutton VR, Niceta M, Ciolfi A, Yamamoto G, Bertola D, Marcelis CL, Lugtenberg D, Bartuli A, Kim C, Hoover-Fong J, Sobreira N, Pauli R, Bacino C, Krakow D, Parboosingh J, Yap P, Kariminejad A, et al.

Am J Hum Genet. 2017 Nov 2;101(5):815-823. doi: 10.1016/j.ajhg.2017.09.019.

PubMed [citation]

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]

Details of each submission

From OMIM, SCV000676923.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)


In 14-year-old boy (family 2) and an unrelated 4-year-old girl (family 7) with the corner fracture type of spondylometaphyseal dysplasia (SMDCF; 184255), Lee et al. (2017) identified heterozygosity for a c.367T-C transition (c.367T-C, NM_212482.2) in the FN1 gene (chr2:g.216,298,095A-G; GRCh37), resulting in a cys123-to-arg (C123R) substitution at a highly conserved residue involved in a disulfide bond within fibronectin domain I-2 in the N-terminal assembly domain. The mutation occurred de novo in both children, and was not found in the ExAC database.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From SIB Swiss Institute of Bioinformatics, SCV000883266.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)


This variant is interpreted as Likely Pathogenic, for Spondylometaphyseal dysplasia, corner fracture type, autosomal dominant. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29100092). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. Replaces a cysteine involved in disulfid (http://www.uniprot.org/uniprot/P02751).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novounknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024