chr11-65870650-C-T

Variant names:

• chr11-65870650-C-T
• rs193302867
• NM_016938.5:c.376G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_016938.5(EFEMP2):​c.376G>A​(p.Glu126Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E126V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.91
• Publications: 13 publications found

Genes affected

EFEMP2 (HGNC:3219): (EGF containing fibulin extracellular matrix protein 2) A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

EFEMP2 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal arteriopathy syndrome due to fibulin-4 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thoracic aortic aneurysm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a domain EGF-like 2; calcium-binding (size 40) in uniprot entity FBLN4_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_016938.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-65870649-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39012.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 11-65870650-C-T is Pathogenic according to our data. Variant chr11-65870650-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.376G>A	p.Glu126Lys	missense_variant	Exon 5 of 11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.501G>A		non_coding_transcript_exon_variant	Exon 5 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.376G>A	p.Glu126Lys	missense_variant	Exon 5 of 11	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250772 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461740 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000495 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Pathogenic:5

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 19, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 14, 2024

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1_Mod PM2_Mod PM3_Mod PP3_Supp PS3_Supp -

not provided Pathogenic:3

Jan 11, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Cutis laxa, autosomal recessive, type 1A Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.93
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.92
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193302867; hg19: chr11-65638121; COSMIC: COSV57260234; COSMIC: COSV57260234;