PLS1

protein-coding

plastin 1, the group of EF-hand domain containing

Gene summary

Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. The protein encoded by this gene is a third distinct plastin isoform, which is specifically expressed at high levels in the small intestine. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Feb 2010]

MANE transcript

NM_001145319.2

Inheritance

ClinVar variants

P:4U:115B:25

Top phenotype

Deafness, autosomal dominant 76

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr3:142,596,393-142,713,664

External References & Databases

Ensembl (ENSG00000120756)

Transcript & Mutation Effects

hg38 • Region Span ~117.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal dominant 76MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032917

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

PLS1 was first reported in relation to autosomal dominant nonsyndromic hearing loss (DFNA76) in 2019 (Schrauwen et al., PMID: 30872814). Such hearing loss is typically moderate-to-profound in severity. 5 variants (missense, splicing) that have been reported in at least 6 probands in 4 publications (PMIDs: 30872814, 31397523, 31432506, 36537221) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, zebrafish model, expression-level data; PMIDs: 25124451, 36537221). A mouse model shows hearing loss and disorganized hair cells in mutant mice. A zebrafish model shows that mutants have inner ear structural anomalies and altered behavior in a swimming test. Evidence in mice and gEAR database expression in humans shows that PLS1 is expressed in the hair cells, cochlear duct, and endothelial cells of the ear. In summary, there is moderate evidence supporting this gene disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

hearing loss, autosomal dominant 76STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032917

Submitter: PanelApp Australia

hearing loss, autosomal dominant 76STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032917

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 76AD

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 30872814; 31397523

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLS1 variants in ClinVar

11 Conditions Cataloged

Inborn genetic diseasesTotal: 73

not providedTotal: 46

PLS1-related disorderTotal: 38

Hearing loss, autosomal dominant 76Total: 15

not specifiedTotal: 6

Autosomal dominant nonsyndromic hearing lossTotal: 3

Hearing impairmentTotal: 2

Bilateral sensorineural hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001145319.2. 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			1 clinvar	15 clinvar	1 clinvar	17
missense		3 clinvar	104 clinvar	5 clinvar	4 clinvar	116
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		1 clinvar	7 clinvar			8
Total	0	4	115	20	5	144

Highest pathogenic variant AF is 6.8411714e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 192 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001145319.2	RefSeq	NP_001138791.1	15	MANE Select
ENST00000457734.7	Ensembl	ENSP00000387890.2	15	MANE Select
NM_001172312.2	RefSeq	NP_001165783.1	15	Standard
NM_002670.3	RefSeq	NP_002661.2	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

intestinal D-glucose absorption
regulation of microvillus length
positive regulation of multicellular organism growth
actin filament bundle assembly
actin filament network formation

Molecular Function

structural constituent of cytoskeleton
calcium ion binding
actin filament binding

Cellular Component

cytoplasm
actin filament
brush border
actin filament bundle
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337777
Coding exons: 15
Length: 117278
Individuals with no LoFs: 125679
Homozygous LoFs: 0
Heterozygous LoFs: 68
Defined: 125747
p: 0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	252	327	0.770	0.0000161	4160
Missense (PolyPhen)		77	111.82	0.68861		1451
Synonymous	1.16	104	120	0.866	0.00000605	1165
Loss of Function	3.05	14	32.8	0.426	0.00000171	412

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00052	0.00052	rare
South Asian	0.000033	0.000033	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actin-bundling protein in the absence of calcium.;

Recessive Scores

pRec: 0.163

Intolerance Scores

LoFtool: 0.0938
RVIS EVS: -0.4
RVIS percentile EVS: 26.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.786

Gene Damage Prediction

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