Submissions for variant NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)

dbSNP: rs119489102

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000005757	SCV002301387	likely pathogenic	Cutis laxa, autosomal recessive, type 1B	2022-06-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EFEMP2 function (PMID: 27339457). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5424). This missense change has been observed in individual(s) with clinical features of cutis laxa (PMID: 17937443; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the EFEMP2 protein (p.Arg279Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005757	SCV002571764	likely pathogenic	Cutis laxa, autosomal recessive, type 1B	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: EFEMP2 c.835C>T (p.Arg279Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Molecular dynamic simulation studies have demonstrated that the introduction of a cysteine in this variant should have a major impact on protein structure by disrupting or changing cysteine bridges. Consistently, this variant was shown to form a dimer band upon immunoblot analysis in serum-free medium (Sasaki_2016). The variant was absent in 251214 control chromosomes. c.835C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Autosomal Recessive Cutis Laxa and this report continues to be cited by others (example, Dasouki_2007 cited in Renard_2010, Sawyer_2013, Kappanayil_2012, Thomas_2021). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating decreased secretion in transfected mouse fibroblasts (Sasaki_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000005757	SCV000025939	pathogenic	Cutis laxa, autosomal recessive, type 1B	2010-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000032275	SCV000055910	not provided	Cutis laxa, autosomal recessive, type 1A		no assertion provided	literature only