Submissions for variant NM_016938.5(EFEMP2):c.1188C>T (p.Ser396=)

gnomAD frequency: 0.00178  dbSNP: rs2234473

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000554306	SCV000373175	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554306	SCV000652044	benign	Cutis laxa, autosomal recessive, type 1B	2025-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589385	SCV000699426	benign	not provided	2017-07-14	criteria provided, single submitter	clinical testing	Variant summary: The EFEMP2 c.1188C>T (p.Ser396Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may create a new binding site for SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 240/120628 control chromosomes from ExAC, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.011343 (74/6524). This frequency is about 101 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Similar frequency in European (Finnish) subpopulation (0.01098; 283/25780 chromosomes) has also been detected in gnomAD database, including 2 homozygotes. One clinical diagnostic laboratory (via ClinVar) has classified this variant as uncertain significance without evidence to independently evaluate. To our knowledge, this variant has not been published in affected individuals in literature. Taken together, this variant is classified as benign.
GeneDx	RCV000589385	SCV000719134	likely benign	not provided	2021-04-22	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000554306	SCV000744891	likely benign	Cutis laxa, autosomal recessive, type 1B	2017-06-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000554306	SCV000883778	benign	Cutis laxa, autosomal recessive, type 1B	2023-04-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589385	SCV001500474	likely benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	EFEMP2: BP4, BP7
Ambry Genetics	RCV002338879	SCV002638955	benign	Cardiovascular phenotype	2019-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003485575	SCV004240549	benign	Familial thoracic aortic aneurysm and aortic dissection	2023-03-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000554306	SCV000745735	benign	Cutis laxa, autosomal recessive, type 1B	2015-01-12	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589385	SCV001978289	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957579	SCV004767508	likely benign	EFEMP2-related disorder	2020-09-03	no assertion criteria provided	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).