GSDME

protein-coding

gasdermin E, the group of Gasdermins

Gene summary

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

DFNA5

MANE transcript

NM_001127453.2

Inheritance

ClinVar variants

P:9U:200B:99

Top phenotype

Deafness, autosomal dominant 5

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr7:24,698,355-24,757,940

External References & Databases

Ensembl (ENSG00000105928)

Transcript & Mutation Effects

hg38 • Region Span ~59.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The DFNA5 (GSDME) gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 5/26/2017. This association was made using case-level data only. At least 5 variants shown to cause a skipping of exon 8 have been reported in humans. DFNA5 was first associated with this disease in humans as early as 1998 (Van Laer et al.). Association is seen in at least 7 probands in 6 publications (9771715, 14676472, 14559215, 24933359, 17868390, 24506266). Variants in this gene segregated with disease in 155 additional family members. The mechanism for disease is a heterozygous gain of function, as evidenced by several cell culture model systems (Gregan 2003, Van Laer 2004, Op de Beeck 2011, Van Rossom 2012), that results in an increase in apoptosis. In summary, DFNA5 is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010973

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010973

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010973

Submitter: G2P

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 5AD

Manifestation: Audiologic/Otolaryngologic

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

Comments: The onset of deafness has been described as postlingual

Refs: 5919633; 5919636; 9771715; 12126021; 12408063; 14559215; 14676472; 17868390; 17427029; 17868390; 19911014; 21805831

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GSDME variants in ClinVar

12 Conditions Cataloged

not providedTotal: 272

Inborn genetic diseasesTotal: 109

not specifiedTotal: 75

Autosomal dominant nonsyndromic hearing loss 5Total: 62

GSDME-related disorderTotal: 43

GSDME-related disordersTotal: 2

Nonsyndromic genetic hearing lossTotal: 1

Rare genetic deafnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127453.2. 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 clinvar	59 clinvar	1 clinvar	63
missense		2 clinvar	178 clinvar	29 clinvar	4 clinvar	213
nonsense		1 clinvar	6 clinvar	2 clinvar		9
start loss						0
frameshift	2 clinvar		10 clinvar	4 clinvar		16
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	3 clinvar			7
Total	3	6	200	94	5	308

Highest pathogenic variant AF is 0.000026018726

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127453.2	RefSeq	NP_001120925.1	9	MANE Select
ENST00000645220.1	Ensembl	ENSP00000494186.1	9	MANE Select
NM_001127454.2	RefSeq	NP_001120926.1	7	Standard
NM_001438059.1	RefSeq	NP_001424988.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
cell death
negative regulation of cell population proliferation
positive regulation of MAPK cascade
inner ear receptor cell differentiation

Molecular Function

phosphatidylinositol-4,5-bisphosphate binding
cardiolipin binding

Cellular Component

cytosol
plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342947
Coding exons: 9
Length: 71273
Individuals with no LoFs: 125082
Homozygous LoFs: 8
Heterozygous LoFs: 658
Defined: 125748
p: 0.00265

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.842	304	265	1.15	0.0000155	3214
Missense (PolyPhen)		94	76.231	1.2331		1091
Synonymous	-0.866	128	116	1.10	0.00000763	1015
Loss of Function	1.12	16	21.6	0.741	0.00000110	241

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.0019	0.0019	notable
Ashkenazi Jewish	0.032	0.032	notable
East Asian	0.0022	0.0022	notable
Finnish	0.0040	0.0040	notable
European (Non-Finnish)	0.00099	0.00099	rare
South Asian	0.00049	0.00049	rare
Other	0.0042	0.0042	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the TP53-regulated cellular response to DNA damage probably by cooperating with TP53 (PubMed:16897187, PubMed:18223688). {ECO:0000269|PubMed:16897187, ECO:0000269|PubMed:18223688}.;
Disease: DISEASE: Deafness, autosomal dominant, 5 (DFNA5) [MIM:600994]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:19911014, ECO:0000269|PubMed:24506266, ECO:0000269|PubMed:26236191, ECO:0000269|PubMed:9771715}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Is a tumor suppressor gene with an important role in colorectal cancer (CRC). {ECO:0000303|PubMed:18223688}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

RVIS EVS: -0.13
RVIS percentile EVS: 44.03

Essentials

Essential (gene trap): N