ClinVar Genomic variation as it relates to human health
NM_016938.5(EFEMP2):c.376G>A (p.Glu126Lys)
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.376G>A (p.Glu126Lys)
Variation ID: 39011 Accession: VCV000039011.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 65870650 (GRCh38) [ NCBI UCSC ] 11: 65638121 (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 Sep 16, 2024 May 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016938.5:c.376G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_058634.4:p.Glu126Lys missense NR_037718.2:n.501G>A non-coding transcript variant NC_000011.10:g.65870650C>T NC_000011.9:g.65638121C>T NG_012304.2:g.7285G>A - Protein change
- E126K
- Other names
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- Canonical SPDI
- NC_000011.10:65870649:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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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not provided (1) |
no classification provided
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- | RCV000032269.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000033125.17 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 15, 2024 | RCV000724423.27 |
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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Pathogenic
(Aug 19, 2021)
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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: SCV001821310.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: EFEMP2 c.376G>A (p.Glu126Lys) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five … (more)
Variant summary: EFEMP2 c.376G>A (p.Glu126Lys) results in a conservative amino acid change located in the EGF-like domain 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 1.2e-05 in 250772 control chromosomes. c.376G>A has been reported in the literature in individuals affected with Autosomal Recessive Cutis Laxa in the homozygous state (Renard_2010, Sawyer_2013) and in the heterozygous state in a patient with TAA (Proost_2015). Additionally, a different variant at the same amino acid position has been reported in patients with Cutix Laxa (p.Glu126Val, Renard_2010). Experimental evidence has shown the variant to impact properties of the fibulin-4 protein, including impaired secretion of the protein as well as reduced binding to collagen IV and fibrillin-1, as well as to LTBP1s and LTBP4s (Sasaki_2016, Renard_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 06, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049024.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The EFEMP2 c.376G>A; p.Glu126Lys variant (rs193302867) is reported in the literature in several homozygous individuals affected with cutis laxa and symptoms of an aortopathy (Renard … (more)
The EFEMP2 c.376G>A; p.Glu126Lys variant (rs193302867) is reported in the literature in several homozygous individuals affected with cutis laxa and symptoms of an aortopathy (Renard 2010, Sawyer 2013). Several heterozygous individuals with this variant were also reported with hypermobility or hip dysplasia, although at least one heterozygous carrier is reported healthy (Sawyer 2013). This variant is found on only three chromosomes (3/250772 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamate at codon 126 is highly conserved, it occurs in an EGF domain in a residue predicted to bind calcium ions, and computational analyses predict that this variant is deleterious (REVEL: 0.955). Consistent with these predictions, functional studies demonstrate that the variant protein is poorly secreted and incorporated in the extracellular matrix, has reduced affinity for binding partner proteins, and is susceptible to proteases (Sasaki 2016, Sasaki 2019). Additionally, another amino acid substitution at this codon (p.Glu126Val) has been reported in trans to a frameshift variant in an individual with cutis laxa (Renard 2010). Based on available information, the p.Glu126Lys variant is considered to be pathogenic. References: Renard M et al. Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur J Hum Genet. 2010 Aug;18(8):895-901. Sasaki T et al. Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa. Matrix Biol. 2016 Dec;56:132-149. Sasaki T et al. Molecular dynamics simulations on human fibulin-4 mutants D203A and E126K reveal conformational changes in EGF domains potentially responsible for enhanced protease lability and impaired extracellular matrix assembly. Biochim Biophys Acta Proteins Proteom. 2019 Sep;1867(9):748-756. Sawyer SL et al. Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4. Am J Med Genet A. 2013 May;161A(5):1148-53. (less)
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Pathogenic
(Jan 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000231150.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(Dec 15, 2023)
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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: SCV004294869.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 126 of the EFEMP2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 126 of the EFEMP2 protein (p.Glu126Lys). This variant is present in population databases (rs193302867, gnomAD 0.003%). This missense change has been observed in individuals with EFEMP2-related conditions (PMID: 20389311, 23532871, 24276535). ClinVar contains an entry for this variant (Variation ID: 39011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EFEMP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EFEMP2 function (PMID: 27339457). This variant disrupts the p.Glu126 amino acid residue in EFEMP2. Other variant(s) that disrupt this residue have been observed in individuals with EFEMP2-related conditions (PMID: 20389311), which suggests that this may be a clinically significant amino acid residue. 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. (less)
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Pathogenic
(Nov 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500475.21
First in ClinVar: Mar 14, 2021 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001826195.2
First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024 |
Comment:
Reported in the homozygous state in two unrelated patients with arterial tortuosity and other features consistent with autosomal recessive cutis laxa (PMID: 20389311, 23532871); Not … (more)
Reported in the homozygous state in two unrelated patients with arterial tortuosity and other features consistent with autosomal recessive cutis laxa (PMID: 20389311, 23532871); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant leads to reduced levels of secreted protein (PMID: 27339457); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23532871, 31125616, 31589614, 36351433, 24276535, 34901216, 25907466, 35456902, 21563328, 27339457, 20389311) (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: SCV000056906.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 26, 2022 |
Comment on evidence:
In a 20-year-old woman with velvety skin and severe arterial tortuosity, aneurysm, and stenosis (ARCL1B; 614437), originally reported by Ades et al. (1996), Renard et … (more)
In a 20-year-old woman with velvety skin and severe arterial tortuosity, aneurysm, and stenosis (ARCL1B; 614437), originally reported by Ades et al. (1996), Renard et al. (2010) identified homozygosity for a 376G-A transition in exon 5 of the EFEMP2 gene, resulting in a glu126-to-lys (E126K) substitution at an evolutionarily conserved residue in the DINE consensus sequence of the second cbEGF-like domain. The mutation was not found in 200 control chromosomes. Immunoblotting experiments on dermal fibroblast culture medium showed only a slightly diminished amount of fibulin-4 compared to control, which the authors suggested was consistent with the longer survival of the patient. In addition, immunoblotting after TGFB (190180) stimulation of patient fibroblast cultures indicated a significantly increased phosphorylated SMAD2 (601366) signal compared to controls, suggesting that mutation in FBLN4 has an effect on the TGFB signaling pathway. (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: SCV000055904.2
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 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
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 |
Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. | Proost D | Human mutation | 2015 | PMID: 25907466 |
Severe aortopathy due to fibulin-4 deficiency: molecular insights, surgical strategy, and a review of the literature. | Hebson C | European journal of pediatrics | 2014 | PMID: 24276535 |
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 |
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 |
Clinicopathologic findings in congenital aneurysms of the great vessels. | Adès LC | American journal of medical genetics | 1996 | PMID: 8985490 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EFEMP2 | - | - | - | - |
Text-mined citations for rs193302867 ...
HelpRecord last updated Sep 17, 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.