rs377286138
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_018100.4(EFHC1):c.1306C>T(p.Arg436Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_018100.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFHC1 | NM_018100.4 | c.1306C>T | p.Arg436Cys | missense_variant | 8/11 | ENST00000371068.11 | |
EFHC1 | NM_001172420.2 | c.1249C>T | p.Arg417Cys | missense_variant | 9/12 | ||
EFHC1 | NR_033327.2 | n.2632C>T | non_coding_transcript_exon_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFHC1 | ENST00000371068.11 | c.1306C>T | p.Arg436Cys | missense_variant | 8/11 | 1 | NM_018100.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251322Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135832
GnomAD4 exome AF: 0.000109 AC: 160AN: 1461650Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79AN XY: 727128
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2013 | p.Arg436Cys (R436C) CGC>TGC: c.1306 C>T in exon 8 of the EFHC1 gene (NM_018100.3). The Arg436Cys missense change in the EFHC1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Cysteine residue, and the addition of a Cysteine may affect disulfide bonding and the secondary structure of the protein. The variant alters a conserved position in the DM10-3 domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether Arg436Cys is a disease-causing mutation or a rare benign variant.Therefore, based on the currently available information, it is unclear whether R436C is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 03, 2014 | - - |
Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 436 of the EFHC1 protein (p.Arg436Cys). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EFHC1 function (PMID: 28370826). 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) performed at Invitae indicates that this missense variant is expected to disrupt EFHC1 protein function. ClinVar contains an entry for this variant (Variation ID: 198888). This missense change has been observed in individual(s) with myoclonic epilepsy (PMID: 28370826; Invitae). This variant is present in population databases (rs377286138, gnomAD 0.03%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at