3-185519292-A-T

Variant names:

• chr3-185519292-A-T
• rs201249971
• NM_139248.3:c.736T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BS1_Supporting BS2_Supporting

The NM_139248.3(LIPH):​c.736T>A​(p.Cys246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,098 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (6 hom.)
• Consequence: LIPH NM_139248.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.09
• Publications: 21 publications found

Genes affected

LIPH (HGNC:18483): (lipase H) This gene encodes a membrane-bound member of the mammalian triglyceride lipase family. It catalyzes the production of 2-acyl lysophosphatidic acid (LPA), which is a lipid mediator with diverse biological properties that include platelet aggregation, smooth muscle contraction, and stimulation of cell proliferation and motility. [provided by RefSeq, Jul 2008]

LIPH Gene-Disease associations (from GenCC):

• hypotrichosis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286086 (HGNC:58335):

ENSG00000309120 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP5: Variant 3-185519292-A-T is Pathogenic according to our data. Variant chr3-185519292-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000257 (375/1460778) while in subpopulation EAS AF = 0.00879 (349/39692). AF 95% confidence interval is 0.00803. There are 6 homozygotes in GnomAdExome4. There are 192 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPH	NM_139248.3	c.736T>A	p.Cys246Ser	missense_variant	Exon 6 of 10	ENST00000296252.9	NP_640341.1
LIPH	NM_001438651.1	c.646T>A	p.Cys216Ser	missense_variant	Exon 5 of 9		NP_001425580.1
LIPH	NM_001438029.1	c.634T>A	p.Cys212Ser	missense_variant	Exon 5 of 9		NP_001424958.1
LIPH	NM_001438652.1	c.607T>A	p.Cys203Ser	missense_variant	Exon 7 of 11		NP_001425581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPH	ENST00000296252.9	c.736T>A	p.Cys246Ser	missense_variant	Exon 6 of 10	1	NM_139248.3	ENSP00000296252.4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251346 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000257 AC: 375 AN: 1460778 Hom.: 6 Cov.: 29 AF XY: 0.000264 AC XY: 192 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00879 AC: 349 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111088

Other (OTH) AF: 0.0000497 AC: 3 AN: 60340

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152320 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotrichosis 7 Pathogenic:4

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace cysteine with serine at codon 246 of the LIPH protein, p.(Cys246Ser). The cysteine residue is invariant across species (100 vertebrates, UCSC), and forms a crucial disulphide bond in the lipase domain. There is a large physicochemical difference between cysteine and serine. The variant is present in a large population cohort at a frequency of 0.016% (rs201249971, 39/251,346 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.15% in the East Asian population (36/18,394 alleles). The variant is a Japanese founder variant that has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with autosomal recessive woolly hair/hypotrichosis, and segregates with disease in at least one family (PMID: 19892526, 20213768). Additionally, in vitro functional assays show complete abolition of hydrolytic activity and no ability to activate P2Y5 for the variant (PMID: 20213768). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PS3_Supporting, PP1, PP3.

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225403, PMID:19892526). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.956>=0.6). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001552). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Hypotrichosis simplex Pathogenic:1

Oct 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys246Ser variant in LIPH has been reported in the homozygous or compound heterozygous state in >15 individuals with hypotrichosis and segregated with dis ease in 4 affected relatives from 4 families (Shimomura 2009, Shinkuma 2010, Yos himasu 2011, Tanahashi 2013, Hayashi 2014, Ito 2015). This variant has been desc ribed as a common founder variant in the Japanese population. This variant has b een identified in 0.2% (37/17248) of East Asian chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID: 225403). Although this variant has been seen in the g eneral population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p .Cys246Ser variant may impact protein function (Shinkuma 2010); however, these t ypes of assays may not accurately represent biological function. Computational p rediction tools and conservation analysis suggest that the p.Cys246Ser variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for hypotrichosis in an autosomal recessive manner based upon presenc e in affected individuals, segregation studies, and functional evidence. ACMG/AM P Criteria applied: PM3_VeryStrong, PP1_Moderate, PP3, PS3_Supporting.

Woolly hair, autosomal recessive 2, with or without hypotrichosis Pathogenic:1

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.4	H;.
PhyloP100		8.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-9.4	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201249971; hg19: chr3-185237080; COSMIC: COSV56182713; COSMIC: COSV56182713;