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NM_212482.4(FN1):c.718T>G (p.Tyr240Asp) AND Spondylometaphyseal dysplasia - Sutcliffe type

Germline classification:
Likely pathogenic (3 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:
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:
RCV000570760.3

Allele description [Variation Report for NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)]

NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)

Gene:
FN1:fibronectin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)
HGVS:
  • NC_000002.12:g.215428306A>C
  • NG_012196.1:g.12763T>G
  • NM_001306129.2:c.718T>G
  • NM_001306130.2:c.718T>G
  • NM_001306131.2:c.718T>G
  • NM_001306132.2:c.718T>G
  • NM_001365517.2:c.718T>G
  • NM_001365518.2:c.718T>G
  • NM_001365519.2:c.718T>G
  • NM_001365520.2:c.718T>G
  • NM_001365521.2:c.718T>G
  • NM_001365522.2:c.718T>G
  • NM_001365523.2:c.718T>G
  • NM_001365524.2:c.718T>G
  • NM_002026.4:c.718T>G
  • NM_054034.3:c.718T>G
  • NM_212474.3:c.718T>G
  • NM_212476.3:c.718T>G
  • NM_212478.3:c.718T>G
  • NM_212482.4:c.718T>GMANE SELECT
  • NP_001293058.2:p.Tyr240Asp
  • NP_001293059.2:p.Tyr240Asp
  • NP_001293060.2:p.Tyr240Asp
  • NP_001293061.2:p.Tyr240Asp
  • NP_001352446.1:p.Tyr240Asp
  • NP_001352447.1:p.Tyr240Asp
  • NP_001352448.1:p.Tyr240Asp
  • NP_001352449.1:p.Tyr240Asp
  • NP_001352450.1:p.Tyr240Asp
  • NP_001352451.1:p.Tyr240Asp
  • NP_001352452.1:p.Tyr240Asp
  • NP_001352453.1:p.Tyr240Asp
  • NP_002017.2:p.Tyr240Asp
  • NP_473375.2:p.Tyr240Asp
  • NP_997639.2:p.Tyr240Asp
  • NP_997641.2:p.Tyr240Asp
  • NP_997643.2:p.Tyr240Asp
  • NP_997647.1:p.Tyr240Asp
  • NP_997647.2:p.Tyr240Asp
  • NC_000002.11:g.216293029A>C
  • NM_212482.2:c.718T>G
  • NM_212482.3:c.718T>G
Protein change:
Y240D; TYR240ASP
Links:
OMIM: 135600.0005; dbSNP: rs1553659131
NCBI 1000 Genomes Browser:
rs1553659131
Molecular consequence:
  • NM_001306129.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306130.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306131.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306132.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365517.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365518.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365519.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365520.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365521.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365522.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365523.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365524.2:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002026.4:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_054034.3:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212474.3:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212476.3:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212478.3:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_212482.4:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Spondylometaphyseal dysplasia - Sutcliffe type
Synonyms:
Sutcliffe type of spondylometaphyseal dysplasia; Sutcliffe SMD; Spondylometaphyseal dysplasia, 'corner fracture' type
Identifiers:
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)
OriginMethodCitations
SCV000676922OMIM
no assertion criteria provided
Pathogenic
(Dec 28, 2017)
germlineliterature only

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

SCV000883165SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 15, 2018)
germlinecuration

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

SCV001364087GeneReviews
no classification provided
not providedgermlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedliterature only, curation

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

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]
PMID:
29100092
PMCID:
PMC5673654
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000676922.1

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

Description

In a mother and daughter (family 4) with the corner fracture type of spondylometaphyseal dysplasia (SMDCF; 184255), Lee et al. (2017) identified heterozygosity for a c.718T-G transversion (c.718T-G, NM_212482.2) in the FN1 gene (chr2:g.216,293,029A-C; GRCh37), resulting in a tyr240-to-asp (Y240D) substitution at a highly conserved residue involved in a disulfide bond within fibronectin domain I-5 in the N-terminal assembly domain. The mutation was not found in an unaffected daughter or in the ExAC database. Western blot analysis of conditioned cell-culture medium from transfected HEK293 cells showed significantly reduced to undetectable secretion of the Y240D mutant compared to wildtype, and immunofluorescence analysis demonstrated increased intracellular retention of the mutant protein.

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

From SIB Swiss Institute of Bioinformatics, SCV000883165.1

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

Description

This variant is interpreted as Likely Pathogenic, for Spondylometaphyseal dysplasia, corner fracture type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29100092). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29100092).

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

From GeneReviews, SCV001364087.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 29, 2023