Submissions for variant NM_016938.5(EFEMP2):c.728-3C>T

gnomAD frequency: 0.00041  dbSNP: rs377139656

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001712623	SCV000716201	likely benign	not provided	2021-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000649948	SCV000771784	uncertain significance	Cutis laxa, autosomal recessive, type 1B	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the EFEMP2 gene. It does not directly change the encoded amino acid sequence of the EFEMP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377139656, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EFEMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 507578). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000649948	SCV001156955	uncertain significance	Cutis laxa, autosomal recessive, type 1B	2019-10-15	criteria provided, single submitter	clinical testing	The EFEMP2 c.728-3C>T variant (rs377139656), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 507578). This variant is found in the general population with an overall allele frequency of 0.024% (67/282510 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict conflicting effects on the nearby canonical acceptor site. Without functional studies the effect on splicing is unknown. Due to limited information, the clinical significance of the c.728-3C>T variant is uncertain at this time.
Illumina Laboratory Services, Illumina	RCV000649948	SCV001263857	uncertain significance	Cutis laxa, autosomal recessive, type 1B	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002384320	SCV002671538	uncertain significance	Cardiovascular phenotype	2023-09-07	criteria provided, single submitter	clinical testing	The c.728-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 7 in the EFEMP2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003927964	SCV004746159	likely benign	EFEMP2-related condition	2019-05-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).