LINS1

protein-coding

lines homolog 1

Gene summary

The Drosophila segment polarity gene lin encodes a protein, lines, which plays important roles in development of the epidermis and hindgut. This gene encodes a protein containing a lines-like domain. This gene is located on chromosome 15 and clustered with the gene encoding ankyrin repeat and SOCS box-containing protein 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

Previous symbols:

LINS
MRT27

MANE transcript

NM_001040616.3

Inheritance

ClinVar variants

P:41U:70B:51

Top phenotype

Intellectual developmental disorder, autosomal recessive 27

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr15:100,559,369-100,603,230

External References & Databases

Ensembl (ENSG00000140471)

Transcript & Mutation Effects

hg38 • Region Span ~43.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual disability, autosomal recessive 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013702

Submitter: G2P

intellectual disability, autosomal recessive 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013702

Submitter: PanelApp Australia

intellectual disability, autosomal recessive 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013702

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*LINS1* variants were first reported in connection to autosomal recessive neurodevelopmental disorder in 2011 by a study identifying candidate genes for autosomal recessive intellectual disability (Najmabadi H et al., PMID: 21937992). Common phenotypes for individuals with *LINS1* variants include intellectual disability, autistic features, hyperactive behavior, stereotypical movements, and mutism. Additionally, some patients exhibited muscular hypotonia, schizophrenia, anxiety, and features of Worster-Drought syndrome (described as a form of cerebral palsy affecting muscles of the mouth and throat) including drooling, dysphagia, and impaired tongue movement. Given the spectrum of neurodevelopmental features observed, the gene is curated under “complex neurodevelopmental disorder” (http://purl.obolibrary.org/obo/MONDO_0100038). Eight homozygous variants of various types (frameshift (2), nonsense (4), splicing (1), and missense (1)), reported in 15 individuals in seven publications have been included in this curation (PMIDs: 21937992, 23773660, 28181389, 30090841, 32802957, 32499722, 34450347). The presumed mechanism of pathogenicity based on published evidence is loss of function. The maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between *LINS1* and autosomal recessive complex neurodevelopmental disorder. 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 Intellectual Disability and Autism expert panel on February 7, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 27AR

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

Refs: 21937992; 23773660

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LINS1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 80

not providedTotal: 68

Intellectual disability, autosomal recessive 27Total: 52

not specifiedTotal: 27

LINS1-related disorderTotal: 6

AutismTotal: 1

MicrocephalyTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040616.3. 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				37 clinvar		37
missense		1 clinvar	66 clinvar	13 clinvar	1 clinvar	81
nonsense	3 clinvar	7 clinvar	1 clinvar			11
start loss						0
frameshift	7 clinvar	18 clinvar	3 clinvar			28
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar				5
Total	11	30	70	50	1	162

Highest pathogenic variant AF is 0.000077492565

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001040616.3	RefSeq	NP_001035706.2	6	MANE Select
ENST00000314742.13	Ensembl	ENSP00000318423.8	6	MANE Select
NM_001352507.2	RefSeq	NP_001339436.1	3	Standard
NM_001352508.2	RefSeq	NP_001339437.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cognition

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000314742
Coding exons: 6
Length: 43862
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.684	427	389	1.10	0.0000189	5010
Missense (PolyPhen)		104	100.13	1.0387		1453
Synonymous	0.0262	143	143	0.997	0.00000733	1415
Loss of Function	1.70	14	22.8	0.615	9.52e-7	342

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000090	0.000087	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00033	0.00031	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0873

Intolerance Scores

RVIS EVS: 1.03
RVIS percentile EVS: 91.09

Essentials

Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0978