MYO5A

protein-coding

myosin VA, the group of Myosin heavy chains, class V

Gene summary

This gene is one of three myosin V heavy-chain genes, belonging to the myosin gene superfamily. Myosin V is a class of actin-based motor proteins involved in cytoplasmic vesicle transport and anchorage, spindle-pole alignment and mRNA translocation. The protein encoded by this gene is abundant in melanocytes and nerve cells. Mutations in this gene cause Griscelli syndrome type-1 (GS1) and neuroectodermal melanolysosomal disease, or Elejalde disease. [provided by RefSeq, Sep 2023]

Previous symbols:

MYH12

MANE transcript

NM_001382347.1

Inheritance

ClinVar variants

P:12U:262B:124

Top phenotype

Griscelli syndrome, type 1

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr15:52,307,281-52,529,132

External References & Databases

Ensembl (ENSG00000197535)

Transcript & Mutation Effects

hg38 • Region Span ~221.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Griscelli syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008962

Submitter: PanelApp Australia

Griscelli syndrome type 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008962

Submitter: Ambry Genetics

Griscelli syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008962

Submitter: ClinGen

The MYO5A gene is located on chromosome 15 at 15q21.2 and encodes myosin Va, a member of the unconventional myosin family. Myosin Va is a processive molecular motor that is described to be responsible for the actin-dependent transport of different types of organelles. The protein encoded by this gene is abundant in melanocytes and nerve cells. Mutations in MYO5A gene was first reported in relation to autosomal recessive Griscelli syndrome, type 1 (GS1) in 1997 (Pastural et al., PMID: 9207796). GS1 represents hypomelanosis with a primary neurologic deficit and without immunologic impairment. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (4 nonsense, 1 frameshift, 1 intragenic deletion) reported in six unrelated probands in five publications (PMID 9207796, Pastural et al., 2000, PMID: 10704277, Menasche et al., 2003, PMID: 12897212, Thomas et al., 2009, PMID: 19318926, Abd Elmaksoud et al. 2020, PMID 32275080). The gene-disease association is supported by myosin Va biochemical function (Wu et al., 1998), MYO5A expression in human skin cells (Lambert et al., 1998, PMID 9826529) and human cerebellum (Souza et al., 2013, PMID 23558932), functional alteration of MYO5A in human epidermal melanocytes (Van Gele et al., 2008, PMID: 18401430), and mouse models that reproduce part of the human phenotype (Provance et al. 1996, PMID 8962090, Takagishi et al. 2006, PMID 1718550). In summary, MYO5A is definitively associated with autosomal recessive Griscelli syndrome type 1. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 26Jan2021 (SOP Version 8).

Griscelli syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008962

Submitter: G2P

Griscelli syndrome type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012220

Submitter: Orphanet

Griscelli syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008962

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Griscelli syndrome, type 1AR

Manifestation: Dermatologic; 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

Refs: 9207796; 10704277; 12452176

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYO5A variants in ClinVar

15 Conditions Cataloged

not providedTotal: 223

Inborn genetic diseasesTotal: 205

not specifiedTotal: 138

Griscelli syndrome type 1Total: 29

MYO5A-related disorderTotal: 28

Intellectual disabilityTotal: 7

Dystonic disorderTotal: 1

Cerebellar cortical atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001382347.1. 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	104 clinvar	4 clinvar	111
missense	1 clinvar	2 clinvar	248 clinvar	14 clinvar	2 clinvar	267
nonsense	5 clinvar	1 clinvar	4 clinvar			10
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)	2 clinvar		7 clinvar			9
Total	8	4	262	118	6	398

Highest pathogenic variant AF is 0.0000018586255

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001382347.1	RefSeq	NP_001369276.1	42	MANE Select
ENST00000399233.7	Ensembl	ENSP00000382179.4	42	MANE Select
NM_000259.3	RefSeq	NP_000250.3	41	Standard
NM_001142495.2	RefSeq	NP_001135967.2	40	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Translocation of GLUT4 to the plasma membrane

Biological Process

exocytosis
post-Golgi vesicle-mediated transport
chemical synaptic transmission
visual perception
vesicle-mediated transport

Molecular Function

microfilament motor activity
RNA binding
calcium ion binding
protein binding
calmodulin binding

Cellular Component

ruffle
photoreceptor outer segment
cytoplasm
lysosome
early endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399231
Coding exons: 41
Length: 221768
Individuals with no LoFs: 124765
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 124801
p: 0.000144

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.10	723	998	0.724	0.0000584	12252
Missense (PolyPhen)		217	382.35	0.56754		4880
Synonymous	1.06	331	356	0.928	0.0000188	3412
Loss of Function	7.71	23	111	0.208	0.00000662	1278

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000065	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00028	0.00028	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament. Involved in melanosome transport. Also mediates the transport of vesicles to the plasma membrane. May also be required for some polarization process involved in dendrite formation. {ECO:0000269|PubMed:10448864}.;
Disease: DISEASE: Griscelli syndrome 3 (GS3) [MIM:609227]: Rare autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes, without other clinical manifestations. {ECO:0000269|PubMed:12897212}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Elejalde syndrome (ELEJAS) [MIM:256710]: Autosomal recessive condition characterized by skin hypopigmentation, the presence of large clumps of pigment in hair shafts, silvery-gray hair, accumulation of melanosomes in melanocytes and primary neurological abnormalities. Elejalde syndrome may be the same entity as Griscelli syndrome type I. {ECO:0000269|PubMed:12058346}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.388

Intolerance Scores

LoFtool: 0.143
RVIS EVS: -1.41
RVIS percentile EVS: 4.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.797

Gene Damage Prediction

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