2-55867075-A-G

Variant names:

• chr2-55867075-A-G
• NM_001039348.3:c.1480T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001039348.3(EFEMP1):​c.1480T>C​(p.Ter494Glnext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFEMP1 NM_001039348.3 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.61

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001039348.3 Downstream stopcodon found after 533 codons.
• PP5: Variant 2-55867075-A-G is Pathogenic according to our data. Variant chr2-55867075-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1294422.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP1	NM_001039348.3	c.1480T>C	p.Ter494Glnext*?	stop_lost	Exon 12 of 12	ENST00000355426.8	NP_001034437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP1	ENST00000355426.8	c.1480T>C	p.Ter494Glnext*?	stop_lost	Exon 12 of 12	1	NM_001039348.3	ENSP00000347596.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Glaucoma 1, open angle, H Pathogenic:1

Mar 18, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the EFEMP1 mRNA. It is expected to extend the length of the EFEMP1 protein by 29 additional amino acid residues. This protein extension has been observed in individual(s) with juvenile‚Äê onset primary open‚Äêangle glaucoma (PMID: 34923728). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1294422). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects EFEMP1 function (PMID: 34923728). For these reasons, this variant has been classified as Pathogenic. -

Glaucoma of childhood Pathogenic:1

Sep 23, 2021

Janey Wiggs Laboratory, Massachusetts Eye and Ear, Harvard Medical School

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The c.1480T>C variant in EFEMP1 causes the stop codon to be lost and adds an additional 29 amino acids to the C-terminus of the protein. This variant has been reported in a Filipino family (Collantes et al, in revision) and segregated with disease in 24 individuals (17 affected) and was absent from last population studies. Additionally, invitro functional studies indicate that c.1480T>C causes intracellular protein aggregation potentially related to disease pathogenesis. In summary the c.1480T>C variant meets criteria to be classified as pathogenic based upon segregation studies, absence from controls and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.90
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.074
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-56094210;