NM_001162498.3(LPAR6):c.565G>A (p.Glu189Lys) AND Hypotrichosis 8

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000001903.6

Allele description [Variation Report for NM_001162498.3(LPAR6):c.565G>A (p.Glu189Lys)]

NM_001162498.3(LPAR6):c.565G>A (p.Glu189Lys)

Genes:

RB1:RB transcriptional corepressor 1 [Gene - OMIM - HGNC]
LPAR6:lysophosphatidic acid receptor 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.2

Genomic location:

Preferred name:

NM_001162498.3(LPAR6):c.565G>A (p.Glu189Lys)

HGVS:

NC_000013.11:g.48411859C>T
NG_009009.1:g.113113C>T
NG_012874.1:g.37846G>A
NG_012874.2:g.37810G>A
NG_127784.1:g.363C>T
NM_000321.3:c.1695+30416C>TMANE SELECT
NM_001162497.3:c.565G>A
NM_001162498.3:c.565G>AMANE SELECT
NM_001377316.2:c.565G>A
NM_001377317.2:c.565G>A
NM_001407165.1:c.1695+30416C>T
NM_005767.7:c.565G>A
NP_001155969.1:p.Glu189Lys
NP_001155970.1:p.Glu189Lys
NP_001364245.1:p.Glu189Lys
NP_001364246.1:p.Glu189Lys
NP_005758.2:p.Glu189Lys
LRG_517:g.113113C>T
NC_000013.10:g.48985995C>T
NM_005767.7:c.565G>A
P43657:p.Glu189Lys

Protein change:

E189K; GLU189LYS

Links:

UniProtKB: P43657#VAR_044328; OMIM: 609239.0006; dbSNP: rs121434309

NCBI 1000 Genomes Browser:

rs121434309

Molecular consequence:

NM_000321.3:c.1695+30416C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001407165.1:c.1695+30416C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001162497.3:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001162498.3:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377316.2:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377317.2:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005767.7:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypotrichosis 8 (HYPT8)
Synonyms:: HYPOTRICHOSIS, LOCALIZED, AUTOSOMAL RECESSIVE 3
Identifiers:: MONDO: MONDO:0010206; MedGen: C3279470; Orphanet: 55654; OMIM: 278150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022060	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 18297072, 18461368
SCV003932426	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	curation	PubMed (4) [See all records that cite these PMIDs] 18461368, 18297072, 36173926, 25741868
SCV005204440	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 34374989, 18461368, 18297072, 36173926 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022060

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 2008)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV003932426

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

curation

PubMed (4)
[See all records that cite these PMIDs]

SCV005204440

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 11, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Spectrum of neuro-genetic disorders in the United Arab Emirates national population.

Saleh S, Beyyumi E, Al Kaabi A, Hertecant J, Barakat D, Al Dhaheri NS, Al-Gazali L, Al Shamsi A.

Clin Genet. 2021 Nov;100(5):573-600. doi: 10.1111/cge.14044. Epub 2021 Aug 19.

PubMed [citation]

PMID:: 34374989

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000022060.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of a Pakistani family with autosomal recessive woolly hair (see 278150), Shimomura et al. (2008) identified a homozygous 565G-A transition in the P2RY5 gene, resulting in a glu189-to-lys (E189K) substitution in the fifth transmembrane domain.

Azeem et al. (2008) identified a homozygous E189K substitution in 3 Pakistani families with autosomal recessive hypotrichosis (278150). The authors noted that none of their patients had woolly hair.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV003932426.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

Description

This variant is interpreted as likely pathogenic for Woolly hair autosomal recessive 1 with or without hypotrichosis. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1); For recessive disorders, detected in trans with a pathogenic variant (PM3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005204440.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: LPAR6 c.565G>A (p.Glu189Lys) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249012 control chromosomes (gnomAD). c.565G>A has been reported in the literature in several homozygous individuals affected with Woolly hair, autosomal recessive, with or without hypotrichosis (examples: Saleh_2021, Shimomura_2008). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies, suggest that the variant may be defective in ligand binding and/or signaling (Yanagida_2023). The following publications have been ascertained in the context of this evaluation (PMID: 36173926, 18461368, 34374989, 18297072). ClinVar contains an entry for this variant (Variation ID: 1829). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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