GM2A

protein-coding

ganglioside GM2 activator, the group of MD-2 related lipid recognition domain containing

Gene summary

This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

MANE transcript

NM_000405.5

Inheritance

ClinVar variants

P:17U:68B:37

Top phenotype

GM2-gangliosidosis, AB variant

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr5:151,212,150-151,270,440

External References & Databases

Ensembl (ENSG00000196743)

Transcript & Mutation Effects

hg38 • Region Span ~58.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tay-Sachs disease AB variantDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010099

Submitter: ClinGen

The relationship between GM2A and Tay Sachs disease, AB variant, a rare, autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 1, 2022. GM2A encodes the GM2 activator protein (GM2AP), a small glycolipid transport protein which is essential for the lysosomal breakdown of GM2-gangliosides, sialic acid-containing glycosphingolipids which are components of the plasma membrane, by hexosaminidase A. A deficiency of the GM2AP results in accumulation of GM2-ganglioside and related glycolipids in the lysosomes of neurons, resulting symptoms indistinguishable from the classical Tay-Sachs phenotype. This includes developmental regression, seizures, exaggerated startle response, and presence of a cherry red spot in the retina (Toro et al, 2020, PMID 20301397). Biallelic variants in GM2A were first reported in patients with Tay Sachs disease, AB variant, in 1991 (Schröder et al, PMID: 1915858). Since then, fifteen families with biallelic variants in GM2A and features of Tay Sachs disease, AB variant, have been reported (İnci et al, 2021, PMID: 33819415, Table1). The mechanism of disease is loss of function. In this curation, data on 10 unique variants (3 nonsense, 1 frameshift, 1 canonical splice site, 3 missense, 2 in frame indels) from 8 probands from 7 publications were collected (Schröder et al, 1991, PMID: 1915858; Schröder et al, 1993, PMID: 8244332; Schepers et al, 1996, PMID: 8900233; Chen et al, 1999, PMID: 10364519; Sheth et al, 2016, PMID: 27402091; Martins et al, 2017, PMID: 28417072; İnci et al, 2021, PMID: 33819415). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of the GM2 activator protein, which is consistent with the biochemical and clinical findings in patients (Smiljanic-Georgijev et al, 1997, PMID: 9187239; Mahuran 1998, PMID: 9714704; Mahuran 1999, PMID: 10571007). The gene product of GM2A is known to interact with the gene product of HEXA, a gene definitively associated with Tay Sachs disease. Lastly, the phenotype of a Gm2a knock out mouse recapitulates the GM2 ganlioside accumulation and some clinical features of Tay Sachs disease (Liu et al, 1997, PMID 9223328). In summary, GM2A is definitively associated with Tay Sachs disease, AB variant. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the Lysosomal Diseases GCEP on August 12, 2022 (SOP v9).

Tay-Sachs disease AB variantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010099

Submitter: Genomics England PanelApp

Tay-Sachs disease AB variantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010099

Submitter: Labcorp Genetics (formerly Invitae)

Tay-Sachs disease AB variantDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010099

Submitter: G2P

Tay-Sachs disease AB variantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010099

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

GM2-gangliosidosis, AB variantAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

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

Refs: 5135907; 10364519; 11339652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GM2A variants in ClinVar

6 Conditions Cataloged

Tay-Sachs disease, variant ABTotal: 120

Inborn genetic diseasesTotal: 32

not providedTotal: 18

GM2A-related conditionTotal: 3

Neurodegenerative illness progressing to crippling dystonia and death with relentless cerebral atrophyTotal: 1

Tay-Sachs diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000405.5. 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			1 clinvar	31 clinvar		32
missense	2 clinvar	3 clinvar	66 clinvar	6 clinvar		77
nonsense	2 clinvar	2 clinvar				4
start loss			1 clinvar			1
frameshift	4 clinvar	3 clinvar				7
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	8	9	68	37	0	122

Highest pathogenic variant AF is 0.0000043390887

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000405.5	RefSeq	NP_000396.2	4	MANE Select
ENST00000357164.4	Ensembl	ENSP00000349687.3	4	MANE Select
NM_001167607.3	RefSeq	NP_001161079.1	4	Standard
ENST00000523004.1	Ensembl	ENSP00000430541.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Degradation pathway of sphingolipids, including diseases
Neutrophil degranulation
Metabolism of lipids
Innate Immune System

Biological Process

glycosphingolipid metabolic process
ganglioside catabolic process
lipid transport
learning or memory
oligosaccharide catabolic process

Molecular Function

lipid transporter activity
phospholipase activator activity
sphingolipid activator protein activity
beta-N-acetylgalactosaminidase activity

Cellular Component

extracellular region
cytoplasmic side of plasma membrane
basolateral plasma membrane
apical plasma membrane
azurophil granule lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357164
Coding exons: 4
Length: 58291
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.298	116	107	1.08	0.00000593	1252
Missense (PolyPhen)		32	34.37	0.93104		436
Synonymous	-1.10	54	44.6	1.21	0.00000255	399
Loss of Function	1.14	3	6.01	0.499	2.53e-7	76

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The large binding pocket can accommodate several single chain phospholipids and fatty acids, GM2A also exhibits some calcium-independent phospholipase activity (By similarity). Binds gangliosides and stimulates ganglioside GM2 degradation. It stimulates only the breakdown of ganglioside GM2 and glycolipid GA2 by beta-hexosaminidase A. It extracts single GM2 molecules from membranes and presents them in soluble form to beta- hexosaminidase A for cleavage of N-acetyl-D-galactosamine and conversion to GM3. {ECO:0000250}.;
Disease: DISEASE: GM2-gangliosidosis AB (GM2GAB) [MIM:272750]: An autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. It is characterized by GM2 gangliosides accumulation in the presence of both normal hexosaminidase A and B. {ECO:0000269|PubMed:1915858, ECO:0000269|PubMed:8244332, ECO:0000269|PubMed:8900233}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.194

Intolerance Scores

LoFtool: 0.376
RVIS EVS: 0.68
RVIS percentile EVS: 84.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.601

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium