11-65870222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016938.5(EFEMP2):c.506G>A(p.Arg169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,613,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: 1.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	6/11	ENST00000307998.11
EFEMP2	NR_037718.2 linkuse as main transcript	n.631G>A		non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	6/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000957

AC:

AN:

250720

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461124

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000565

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 30, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the EFEMP2 protein (p.Arg169His). This variant is present in population databases (rs141310608, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of EFEMP2-related conditions (PMID: 28454995, 29620724, 31127727). ClinVar contains an entry for this variant (Variation ID: 472828). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 16, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	EFEMP2 NM_016938.5 exon 6 p.Arg169His (c.506G>A): This variant has been reported in the literature in one individual with features of a skeletal dysplasia, as well as reported as homozygous in one individual with an unspecified muscle disease (Alfares 2017 PMID:28454995, Maddirevula 2018 PMID:29620724). This variant is also present in 0.01% (23/128572) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-65637693-C-T) and is present in ClinVar (Variation ID:472828). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31127727, 29620724, 28454995) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2022

The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the EFEMP2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a homozygous state in a subject with muscle weakness (Alfares A et al. Mol. Genet. Metab., 2017 06;121:91-95). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

EFEMP2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2023

The EFEMP2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169His. This variant was reported in the homozygous state individuals with connective tissue disorder, scoliosis, joint dislocations, contractures and muscle disorder (Alfares et al. 2017. PubMed ID: 28454995; Maddirevula et al. 2018. PubMed ID: 29620724; Westra et al. 2019. PubMed ID: 31127727). In at least two cases, parents were from a consanguineous marriage. Functionnal characterization was not preformed. This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-65637693-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.080

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.034

T;T;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Uncertain

0.65

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Benign

0.068

T;D;.;D

Polyphen

1.0

D;D;.;.

Vest4

0.65

MVP

0.97

MPC

1.1

ClinPred

0.27

GERP RS

5.4

Varity_R

0.16

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over