NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000726861.10

Allele description [Variation Report for NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp)]

NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp)

Gene:

EFEMP1:EGF containing fibulin extracellular matrix protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.1

Genomic location:

Preferred name:

NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp)

HGVS:

NC_000002.12:g.55871091G>A
NG_009098.1:g.57707C>T
NM_001039348.3:c.1033C>TMANE SELECT
NM_001039349.2:c.1033C>T
NM_001039349.3:c.1033C>T
NP_001034437.1:p.Arg345Trp
NP_001034438.1:p.Arg345Trp
NC_000002.11:g.56098226G>A
NM_001039348.2:c.1033C>T
NM_001039348.3:c.1033C>T
Q12805:p.Arg345Trp

Protein change:

R345W; ARG345TRP

Links:

UniProtKB: Q12805#VAR_009513; OMIM: 601548.0001; dbSNP: rs121434491

NCBI 1000 Genomes Browser:

rs121434491

Molecular consequence:

NM_001039348.3:c.1033C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001039349.3:c.1033C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000703677	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 8, 2016)	germline	clinical testing	Citation Link,
SCV001214457	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10369267, 11384588, 25077532, 30541486, 12242346, 28492532
SCV005325199	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 21, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000703677

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Dec 8, 2016)

germline

clinical testing

Citation Link,

SCV001214457

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005325199

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 21, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy.

Stone EM, Lotery AJ, Munier FL, Héon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF.

Nat Genet. 1999 Jun;22(2):199-202.

PubMed [citation]

PMID:: 10369267

Dominant radial drusen and Arg345Trp EFEMP1 mutation.

Matsumoto M, Traboulsi EI.

Am J Ophthalmol. 2001 Jun;131(6):810-2.

PubMed [citation]

PMID:: 11384588

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000703677.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001214457.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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 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). 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 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV005325199.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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