rs121434491

Variant names:

• chr2-55871091-G-A
• rs121434491
• NM_001039348.3:c.1033C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001039348.3(EFEMP1):​c.1033C>T​(p.Arg345Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,422 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EFEMP1 NM_001039348.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.97

Genes affected

EFEMP1 (HGNC:3218): (EGF containing fibulin extracellular matrix protein 1) This gene encodes a member of the fibulin family of extracellular matrix glycoproteins. Like all members of this family, the encoded protein contains tandemly repeated epidermal growth factor-like repeats followed by a C-terminus fibulin-type domain. This gene is upregulated in malignant gliomas and may play a role in the aggressive nature of these tumors. Mutations in this gene are associated with Doyne honeycomb retinal dystrophy. Alternatively spliced transcript variants that encode the same protein have been described.[provided by RefSeq, Nov 2009]

LOC112268416 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 2-55871091-G-A is Pathogenic according to our data. Variant chr2-55871091-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-55871091-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP1	NM_001039348.3	c.1033C>T	p.Arg345Trp	missense_variant	Exon 10 of 12	ENST00000355426.8	NP_001034437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP1	ENST00000355426.8	c.1033C>T	p.Arg345Trp	missense_variant	Exon 10 of 12	1	NM_001039348.3	ENSP00000347596.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461422 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Doyne honeycomb retinal dystrophy Pathogenic:3

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with Doyne honeycomb degeneration of retina (DHDR) and Malattia leventinese (PMID: 10369267, 25111685, 30541486). Mouse knock-in studies demonstrated that this variant leads to pathophysiological changes to the eye that are similar to the features seen in DHDR (PMID: 17666404). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1033C>T (p.Arg345Trp) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1033C>T (p.Arg345Trp) variant is classified as Pathogenic. -

not provided Pathogenic:3

Dec 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with ocular deposits observed in mouse models and abnormal secretion in in vitro studies (PMID: 17666404, 33542268); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25111685, 22031286, 22159686, 15785976, 26427406, 18791549, 33019987, 10369267, 33542268, 17666404, 27777122, 25077532, 30541486, 33689237, 11384588) -

Dec 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 345 of the EFEMP1 protein (p.Arg345Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Doyne or Malattia Leventinese honeycomb retinal dystrophy (PMID: 10369267, 11384588, 25077532, 30541486). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8072). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EFEMP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EFEMP1 function (PMID: 12242346). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:2

Jan 01, 2006

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	D;D
Vest4		0.84
MutPred		0.65		Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP		0.87
MPC		0.83
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 32

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434491; hg19: chr2-56098226; COSMIC: COSV62615573;