rs119489102
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_016938.5(EFEMP2):c.835C>T(p.Arg279Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_016938.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EFEMP2 | NM_016938.5 | c.835C>T | p.Arg279Cys | missense_variant | Exon 8 of 11 | ENST00000307998.11 | NP_058634.4 | |
EFEMP2 | NR_037718.2 | n.960C>T | non_coding_transcript_exon_variant | Exon 8 of 12 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461708Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727148
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cutis laxa, autosomal recessive, type 1B Pathogenic:3
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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. The variant was absent in 251214 control chromosomes. 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). The following publications have been ascertained in the context of this evaluation (PMID: 20389311, 27339457, 23532871, 17937443, 22943132, 34901216). ClinVar contains an entry for this variant (Variation ID: 5424). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 5424). 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. Experimental studies have shown that this missense change affects EFEMP2 function (PMID: 27339457). 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. -
Cutis laxa, autosomal recessive, type 1A Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at