rs727505029
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000117.3(EMD):c.77T>C(p.Val26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,056,063 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 26)
Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )
Consequence
EMD
NM_000117.3 missense
NM_000117.3 missense
Scores
3
5
9
Clinical Significance
Conservation
PhyloP100: 0.541
Genes affected
EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
26
GnomAD4 exome AF: 0.00000189 AC: 2AN: 1056063Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 1AN XY: 344861
GnomAD4 exome
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2
AN:
1056063
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Cov.:
31
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AC XY:
1
AN XY:
344861
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
26
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Emery-Dreifuss muscular dystrophy 1, X-linked Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Unidad de Genética, Hospital Universitario de Canarias | Sep 18, 2024 | The c.77T>C variant (p.Val26Ala) in the EMD gene involves the change of the amino acid valine to alanine in position 26 of the protein (rs727505029). Both amino acids present slight differences in physicochemical properties (Grantham distance: 64 [0-215]) and it is a moderately conserved residue in the available vertebrate species (PhyloP100 = 0.541). It is present at very low frequency in general population sequencing databases (GnomAD v4.0.1, 1 male hemizygote in non-Finnish Europeans, 0.0001709%) and the in silico pathogenicity predictors used for this variant are inconclusive regarding to the effect that the variant produces on the function of the protein. In the clinical database ClinVar (ID:179659) it is described as uncertain significance by 4 subscribers without conflict of interpretation. The initial description of this variant (Cuenca et al., 2016-PMID: 26899768) occurred in a cohort of 52 patients with dilated cardiomyopathy (DCM) undergoing heart transplantation. In 13 of them, the c.77T>C (p.Val26Ala) variant was detected in the EMD gene and through a haplotype study in 9 of them it was described as a founder variant from Tenerife (Canary Islands, Spain). In our center we have identified it in 25 subjects with DCM. Furthermore, all of them progressed to a DCM phenotype during the fourth decade of life, high penetrance beyond the fifth decade of life, and a high incidence of arrhythmias and heart transplantation due to severe left ventricular dysfunction, as shown in a study conducted in our center (Báez-Ferrer et al. 2024-PMID: 38673666). No Emery-Dreifuss myopathy has been described in any of our patients to this date. For all the above, we classify this variant as LIKELY PATHOGENIC according to the ACMG guidelines (PM2_supporting / PS4_very strong / PP1_strong). - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 24, 2014 | The Val26Ala variant in EMD has not been previously reported in individuals with cardiomyopathy or Emery-Dreifuss muscular dystrophy. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that this variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. Additional information is needed to fully assess the clinical signi ficance of the Val26Ala variant. - |
Emery-Dreifuss muscular dystrophy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 10, 2020 | - - |
X-linked Emery-Dreifuss muscular dystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2025 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 26 of the EMD protein (p.Val26Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 26899768, 38337354). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179659). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EMD protein function with a positive predictive value of 80%. 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2023 | The p.V26A variant (also known as c.77T>C), located in coding exon 1 of the EMD gene, results from a T to C substitution at nucleotide position 77. The valine at codon 26 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in individuals with dilated cardiomyopathy (DCM), including segregating in some families (Cuenca S et al. J Heart Lung Transplant, 2016 05;35:625-35). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D;T
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
T;D
Polyphen
P;.
Vest4
MutPred
Gain of disorder (P = 0.0955);Gain of disorder (P = 0.0955);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at