rs727505029

Positions:

• chrX-154379561-T-C

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMD	NM_000117.3	c.77T>C	p.Val26Ala	missense_variant	1/6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.77T>C	p.Val26Ala	missense_variant	1/6	1	NM_000117.3	ENSP00000358857	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1056063 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 1 AN XY: 344861

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000122

Gnomad4 OTH exome AF: 0.0000225

GnomAD4 genome Cov.: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

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

Oct 06, 2023

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). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179659). 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 EMD protein function. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D;T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.3	D;N
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.94	P;.
Vest4		0.40
MutPred		0.50		Gain of disorder (P = 0.0955);Gain of disorder (P = 0.0955);
MVP		0.79
MPC		0.83
ClinPred		0.93	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727505029; hg19: chrX-153607921;