ClinVar Genomic variation as it relates to human health
NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)
Variation ID: 5424 Accession: VCV000005424.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 65868522 (GRCh38) [ NCBI UCSC ] 11: 65635993 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Aug 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016938.5:c.835C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_058634.4:p.Arg279Cys missense NR_037718.2:n.960C>T non-coding transcript variant NC_000011.10:g.65868522G>A NC_000011.9:g.65635993G>A NG_012304.2:g.9413C>T NG_053116.1:g.13461G>A O95967:p.Arg279Cys - Protein change
- R279C
- Other names
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- Canonical SPDI
- NC_000011.10:65868521:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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EFEMP2 | - | - |
GRCh38 GRCh37 |
432 | 516 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2022 | RCV000005757.9 | |
not provided (1) |
no classification provided
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- | RCV000032275.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jun 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cutis laxa, autosomal recessive, type 1B
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002301387.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EFEMP2 function (PMID: 27339457). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5424). This missense change has been observed in individual(s) with clinical features of cutis laxa (PMID: 17937443; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the EFEMP2 protein (p.Arg279Cys). (less)
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Likely pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cutis laxa, autosomal recessive, type 1B
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571764.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: EFEMP2 c.835C>T (p.Arg279Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of … (more)
Variant summary: EFEMP2 c.835C>T (p.Arg279Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Molecular dynamic simulation studies have demonstrated that the introduction of a cysteine in this variant should have a major impact on protein structure by disrupting or changing cysteine bridges. Consistently, this variant was shown to form a dimer band upon immunoblot analysis in serum-free medium (Sasaki_2016). The variant was absent in 251214 control chromosomes. c.835C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Autosomal Recessive Cutis Laxa and this report continues to be cited by others (example, Dasouki_2007 cited in Renard_2010, Sawyer_2013, Kappanayil_2012, Thomas_2021). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating decreased secretion in transfected mouse fibroblasts (Sasaki_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Aug 01, 2010)
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no assertion criteria provided
Method: literature only
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CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025939.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 26, 2022 |
Comment on evidence:
In an infant girl with cutis laxa, apparent arachnodactyly, and severe systemic vascular abnormalities (ARCL1B; 614437), who died at day 27 of life, Dasouki et … (more)
In an infant girl with cutis laxa, apparent arachnodactyly, and severe systemic vascular abnormalities (ARCL1B; 614437), who died at day 27 of life, Dasouki et al. (2007) identified compound heterozygosity for an 835C-T transition in exon 8 of the EFEMP2 gene, resulting in an arg279-to-cys (R279C) substitution at a highly conserved residue at the end of the fifth cbEGF module, and a 4-bp duplication in exon 10 (1070dupCCGC; 604633.0003), predicted to truncate the protein and replace the last 85 amino acids of the FC domain with an incorrect arg residue. The missense mutation was not found in 50 controls. Analysis of the patient's fibroblasts revealed that fibulin-4 protein was barely detectable in culture medium and not seen in cell extract and matrix, and immunostaining of patient fibroblasts showed a total absence of fibulin-4 fibers from the extracellular matrix. Renard et al. (2010) performed immunohistochemical staining of fibulin-4 on aortic tissue from the patient previously studied by Dasouki et al. (2007) and confirmed the near absence of extracellular fibulin-4 in the aortic wall compared to the control, whereas intracellular staining was similar to that of the control, suggesting that the mutant protein is either not secreted or is secreted into extracellular space to a lesser extent. Immunohistochemical staining for phosphorylated SMAD2 (601366) and CTGF (121009), an effector of TGF-beta (190180) signaling and a TGF-beta-driven gene product, respectively, in patient aorta and lungs showed a more intense and increased nuclear staining compared to control tissues. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive cutis laxa type 1
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055910.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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EFEMP2-Related Cutis Laxa. | Adam MP | - | 2023 | PMID: 21563328 |
Case Report: Occurrence of Severe Thoracic Aortic Aneurysms (Involving the Ascending, Arch, and Descending Segments) as a Result of Fibulin-4 Deficiency: A Rare Pathology With Successful Management. | Thomas P | Frontiers in cardiovascular medicine | 2021 | PMID: 34901216 |
Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa. | Sasaki T | Matrix biology : journal of the International Society for Matrix Biology | 2016 | PMID: 27339457 |
Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4. | Sawyer SL | American journal of medical genetics. Part A | 2013 | PMID: 23532871 |
Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis. | Kappanayil M | Orphanet journal of rare diseases | 2012 | PMID: 22943132 |
Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. | Renard M | European journal of human genetics : EJHG | 2010 | PMID: 20389311 |
Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. | Dasouki M | American journal of medical genetics. Part A | 2007 | PMID: 17937443 |
Text-mined citations for rs119489102 ...
HelpRecord last updated Jun 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.