rs41269557
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_153717.3(EVC):c.1826G>A(p.Arg609Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,553,106 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R609W) has been classified as Uncertain significance.
Frequency
Consequence
NM_153717.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC | NM_153717.3 | c.1826G>A | p.Arg609Gln | missense_variant | 13/21 | ENST00000264956.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.1826G>A | p.Arg609Gln | missense_variant | 13/21 | 1 | NM_153717.3 | P1 | |
EVC | ENST00000506240.1 | n.144G>A | non_coding_transcript_exon_variant | 1/2 | 3 | ||||
EVC | ENST00000515113.1 | n.50G>A | non_coding_transcript_exon_variant | 1/4 | 5 | ||||
CRMP1 | ENST00000506216.5 | n.1647+31837C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00190 AC: 289AN: 152164Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00173 AC: 276AN: 159774Hom.: 0 AF XY: 0.00175 AC XY: 147AN XY: 84206
GnomAD4 exome AF: 0.00319 AC: 4470AN: 1400824Hom.: 6 Cov.: 30 AF XY: 0.00314 AC XY: 2169AN XY: 691078
GnomAD4 genome ? AF: 0.00190 AC: 289AN: 152282Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131AN XY: 74464
ClinVar
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2023 | Variant summary: EVC c.1826G>A (p.Arg609Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 159774 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1826G>A in individuals affected with Ellis-van Creveld syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=6) and likely benign(n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 25, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 27, 2019 | The EVC c.1826G>A; p.Arg609Gln variant (rs41269557), to our knowledge, is not described in the medical literature but is reported as likely benign by several laboratories in ClinVar (Variation ID: 194282). It is observed in the general population at an overall frequency of 0.17% (314/183408 alleles) with increased frequency in the European (Non-Finnish) population (0.36%) in the Genome Aggregation Database. The arginine at codon 609 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic EVC variants are inherited in an autosomal recessive manner associated with Ellis-van Creveld syndrome (MIM: 225500) and in an autosomal dominant manner associated with Weyers acrodental dysostosis (MIM: 193530). - |
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | EVC: BP4, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 13, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2021 | - - |
Ellis-van Creveld syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.1826G>A (p.R609Q) alteration is located in exon 13 (coding exon 13) of the EVC gene. This alteration results from a G to A substitution at nucleotide position 1826, causing the arginine (R) at amino acid position 609 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
EVC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 07, 2022 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at