Submissions for variant NM_016938.5(EFEMP2):c.397G>A (p.Asp133Asn)

dbSNP: rs766172211

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000265641	SCV000373181	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.
GeneDx	RCV000584857	SCV000618985	uncertain significance	not provided	2017-07-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the EFEMP2 gene. The D133N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 5/66126 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The D133N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is only conserved in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
CeGaT Center for Human Genetics Tuebingen	RCV000584857	SCV000692714	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000265641	SCV001566606	uncertain significance	Cutis laxa, autosomal recessive, type 1B	2022-05-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 133 of the EFEMP2 protein (p.Asp133Asn). This variant is present in population databases (rs766172211, gnomAD 0.01%). 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: 305382). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.