Submissions for variant NM_016938.5(EFEMP2):c.376G>A (p.Glu126Lys)

gnomAD frequency: 0.00001  dbSNP: rs193302867

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724423	SCV000231150	pathogenic	not provided	2016-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724423	SCV001500475	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033125	SCV001821310	pathogenic	Cutis laxa, autosomal recessive, type 1B	2021-08-19	criteria provided, single submitter	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.
GeneDx	RCV000724423	SCV001826195	likely pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing	Reported in the homozygous state in two unrelated patients with arterial tortuosity and other features consistent with autosomal recessive cutis laxa (Renard et al., 2010; Sawyer et al., 2013); Reported in ClinVar (ClinVar Variant ID# 39011; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant leads to reduced levels of secreted protein (Sasaki et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31125616, 21563328, 20389311, 23532871, 27339457)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000033125	SCV002049024	pathogenic	Cutis laxa, autosomal recessive, type 1B	2021-01-06	criteria provided, single submitter	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.
Invitae	RCV000033125	SCV004294869	likely pathogenic	Cutis laxa, autosomal recessive, type 1B	2023-12-15	criteria provided, single submitter	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.
GeneReviews	RCV000032269	SCV000055904	not provided	Cutis laxa, autosomal recessive, type 1A		no assertion provided	literature only
OMIM	RCV000033125	SCV000056906	pathogenic	Cutis laxa, autosomal recessive, type 1B	2010-08-01	no assertion criteria provided	literature only