VCV000001828.3 - ClinVar

NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)

Variation ID: 1828 Accession: VCV000001828.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.2 13: 48411988 (GRCh38) [ NCBI UCSC ] 13: 48986124 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Jun 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000321.3:c.1695+30545C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001162498.3:c.436G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001155970.1:p.Gly146Arg	missense
NM_001162497.3:c.436G>A	NP_001155969.1:p.Gly146Arg	missense
NM_001377316.2:c.436G>A	NP_001364245.1:p.Gly146Arg	missense
NM_001377317.2:c.436G>A	NP_001364246.1:p.Gly146Arg	missense
NM_001407165.1:c.1695+30545C>T		intron variant
NM_005767.7:c.436G>A	NP_005758.2:p.Gly146Arg	missense
NC_000013.11:g.48411988C>T
NC_000013.10:g.48986124C>T
NG_009009.1:g.113242C>T
NG_012874.1:g.37717G>A
NG_012874.2:g.37681G>A
NG_127784.1:g.492C>T
LRG_517:g.113242C>T

... more HGVS ... less HGVS

Protein change

G146R

Other names

Canonical SPDI

NC_000013.11:48411987:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA026394 OMIM: 609239.0005 dbSNP: rs121434308 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3636	3797
LPAR6		-	-	GRCh38 GRCh37	-	144

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypotrichosis 8	Likely pathogenic (3)	criteria provided, single submitter	-	RCV000001902.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hypotrichosis 8 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV003932424.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Publications: PubMed (4) PubMed: 18461368‚ 19292720‚ 21426374‚ 36173926 Comment: This variant is interpreted as likely pathogenic for Hypotrichosis 8, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low … (more) This variant is interpreted as likely pathogenic for Hypotrichosis 8, autosomal recessive. 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 upgraded to moderate); For recessive disorders, detected in trans with a pathogenic variant (PM3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting) (less)
Likely pathogenic (Jun 02, 2015)	no assertion criteria provided Method: clinical testing	Hypotrichosis 8 (Autosomal recessive inheritance) Affected status: yes, unknown Allele origin: germline	Baylor Genetics Accession: SCV000328829.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 18461368‚ 25119526 Comment: Our laboratory reported dual molecular diagnoses in AGL (NM_000028.2, c.3836+1G>A) and LPAR6 (NM_005767.4, c.436G>A) in an individual with reported features of motor and speech delay, … (more) Our laboratory reported dual molecular diagnoses in AGL (NM_000028.2, c.3836+1G>A) and LPAR6 (NM_005767.4, c.436G>A) in an individual with reported features of motor and speech delay, seizure disorder, woolly sparse hair and eye brows, and massive hepatomegaly. Thie LPAR6 VUS has been previously reported, but there is not sufficient information to categorize it as disease-causing. (less) Observation 1: Number of individuals with the variant: 1 Age: 0-9 years Sex: female Geographic origin: Afghanistan Observation 2:
Pathogenic (Aug 01, 2011)	no assertion criteria provided Method: literature only	HYPOTRICHOSIS 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022059.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 12, 2018	Publications: PubMed (2) PubMed: 18461368‚ 21426374 Comment on evidence: In affected members of 3 Pakistani families segregating autosomal recessive hypotrichosis (HYPT8; 278150), Azeem et al. (2008) identified a homozygous 436G-A transition in the LPAR6 … (more) In affected members of 3 Pakistani families segregating autosomal recessive hypotrichosis (HYPT8; 278150), Azeem et al. (2008) identified a homozygous 436G-A transition in the LPAR6 gene, resulting in a gly146-to-arg (G146R) substitution in the fourth transmembrane domain. In affected members of 3 Pakistani families with features of hypotrichosis, Khan et al. (2011) identified homozygosity for the G146R mutation in LPAR6. (less)

Comment:

This variant is interpreted as likely pathogenic for Hypotrichosis 8, autosomal recessive. 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 upgraded to moderate); For recessive disorders, detected in trans with a pathogenic variant (PM3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting)

Comment:

Our laboratory reported dual molecular diagnoses in AGL (NM_000028.2, c.3836+1G>A) and LPAR6 (NM_005767.4, c.436G>A) in an individual with reported features of motor and speech delay, seizure disorder, woolly sparse hair and eye brows, and massive hepatomegaly. Thie LPAR6 VUS has been previously reported, but there is not sufficient information to categorize it as disease-causing.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cell-trafficking impairment in disease-associated LPA6 missense mutants and a potential pharmacoperone therapy for autosomal recessive woolly hair/hypotrichosis.	Yanagida K	Human molecular genetics	2023	PMID: 36173926
In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis.	Raza SI	PloS one	2014	PMID: 25119526
Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan.	Khan S	Clinical and experimental dermatology	2011	PMID: 21426374
Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families.	Tariq M	The British journal of dermatology	2009	PMID: 19292720
Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3).	Azeem Z	Human genetics	2008	PMID: 18461368

Text-mined citations for rs121434308 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 01, 2024

ClinVar Genomic variation as it relates to human health

NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434308 ...