rs145300726
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_153717.3(EVC):āc.928C>Gā(p.Leu310Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L310L) has been classified as Likely benign.
Frequency
Consequence
NM_153717.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC | NM_153717.3 | c.928C>G | p.Leu310Val | missense_variant | 7/21 | ENST00000264956.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.928C>G | p.Leu310Val | missense_variant | 7/21 | 1 | NM_153717.3 | P1 | |
EVC | ENST00000509451.1 | c.928C>G | p.Leu310Val | missense_variant | 7/12 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461770Hom.: 0 Cov.: 38 AF XY: 0.0000193 AC XY: 14AN XY: 727190
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74420
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 310 of the EVC protein (p.Leu310Val). This variant is present in population databases (rs145300726, gnomAD 0.004%). This missense change has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 23220543; 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: 546095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EVC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 23220543) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | Variant summary: EVC c.928C>G (p.Leu310Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. However, several computational tools predict a significant impact on normal splicing: four predict the variant creates a 5' donor site, and one predicts the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.928C>G has been reported in the literature in at least one compound heterozygous individual affected with Ellis-van Creveld syndrome (e.g., D'Asdia_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 23220543). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 1; Likely pathogenic, n = 1; Pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ellis-van Creveld syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at