ERMARD
protein-codingER membrane associated RNA degradation
Gene summary
The protein encoded by this gene contains 2 transmembrane domains near the C-terminus and is localized in the endoplasmic reticulum. Knockout of this gene in developing rat brain showed that it may be involved in neuronal migration. Mutations in this gene are associated with periventricular nodular heterotopia-6 (PVNH6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]
- C6orf70
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020341
Submitter: ClinGen
*ERMARD *variants were first reported in connection with autosomal dominant periventricular nodular heterotopia in 2013 (Conti et al., 2013 PMID: 24056535). Affected individuals are characterized by strabismus, delayed psychomotor development, seizures, delayed speech, hypsarrhythmia, and periventricular nodular heterotopia(PNH). The presumed mechanism of pathogenicity is loss of function. One de novo missense mutation from one publication has been included in this curation (Conti et al., 2013 PMID: 24056535). Variant pathogenicity is supported by reduction of the mutant protein in comparison with wild-type. Immunocytochemistry reveals that, while in cells transfected with wild-type construct C6orf70 was distributed in a puncta-like pattern, transfection with the mutant construct generated a predominantly dispersed pattern of staining, suggesting that this mutation also alters the subcellular distribution of Ermard proteins. Statistical analysis revealed a significant switching from puncta-like to diffuse pattern of staining due to this variant. An additional proband submitted in ClinVar harboring a frameshift variant with PNH was included in this curation (SCV002012038.1, 3 Billion Internal data). A total of 1.1 genetic evidence points was reached. This gene disease relationship is also supported by expression and rescue in a non-human model organism (PMID: 24056535). Conti et al., 2013 also identified 12 patients exhibiting abnormal brain development with periventricular nodular heterotopia, harbouring partially overlapping deletions of different extent in 6q25-qter and sharing a common 1.2 Mb minimal critical deletion in 6q27. Although these patients present with PNH, they were not included in this curation due to the multigene deletion. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Brain Malformations expert panel on May 28th, 2024 (SOP Version 10).
Inheritance Pattern: Unknown
Disease ID:MONDO:0014240
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014240
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014240
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014240
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014240
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020341
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ERMARD variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018341.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 52 | 2 | 57 | ||
| missense | 1 | 157 | 36 | 4 | 198 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 0 | |||||
| frameshift | 12 | 2 | 14 | |||
| splice donor/acceptor (+/-2bp) | 2 | 9 | 11 | |||
| Total | 1 | 3 | 183 | 90 | 6 | 283 |
Highest pathogenic variant AF is 0.0000061564983
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060811.1 | 18 | MANE Select | |
| Ensembl | ENSP00000355735.3 | 18 | MANE Select | |
| RefSeq | NP_001265460.1 | 18 | Standard | |
| RefSeq | NP_001265461.1 | 15 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- multicellular organism development
- biological_process
Molecular Function
- molecular_function
Cellular Component
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366773
- Coding exons
- 18
- Length
- 29963
- Individuals with no LoFs
- 125370
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 377
- Defined
- 125748
- p
- 0.00150
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.320 | 384 | 367 | 1.05 | 0.0000203 | 4410 |
| Missense (PolyPhen) | 96 | 101.71 | 0.9439 | 1268 | ||
| Synonymous | -0.398 | 145 | 139 | 1.04 | 0.00000800 | 1298 |
| Loss of Function | 1.44 | 29 | 38.6 | 0.750 | 0.00000199 | 464 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00092 | 0.00092 | rare |
| Latino/Admixed American | 0.0030 | 0.0030 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0012 | 0.0011 | notable |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.0017 | 0.0017 | notable |
| South Asian | 0.0012 | 0.0012 | notable |
| Other | 0.0016 | 0.0016 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play a role in neuronal migration during embryonic development. {ECO:0000269|PubMed:24056535}.;
- Disease
- DISEASE: Periventricular nodular heterotopia 6 (PVNH6) [MIM:615544]: A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH6 results in delayed psychomotor development, delayed speech, strabismus, and onset of seizures with hypsarrhythmia in early infancy. {ECO:0000269|PubMed:24056535}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0933
Intolerance Scores
- RVIS EVS
- 1.43
- RVIS percentile EVS
- 94.99
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |