Genetic Variant LSS:p.Trp581Arg (chr21-46195752-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1PM1PM2PP3_Strong

The NM_002340.6(LSS):c.1741T>A(p.Trp581Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.84

Publications

8 publications found

Variant links:

Genes affected

LSS (HGNC:6708): (lanosterol synthase) The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

LSS Gene-Disease associations (from GenCC):

alopecia-intellectual disability syndrome 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 44
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypotrichosis 14
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
hypotrichosis simplex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive palmoplantar keratoderma and congenital alopecia
Inheritance: AR Classification: LIMITED Submitted by: G2P

LSS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS1

Transcript NM_002340.6 (LSS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 221227

PM1

In a site Transition state stabilizer (size 0) in uniprot entity LSS_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LSS	NM_002340.6 link	c.1741T>A	p.Trp581Arg	missense_variant	Exon 19 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 link	c.1741T>A	p.Trp581Arg	missense_variant	Exon 19 of 23		NP_001001438.1
LSS	NM_001145436.2 link	c.1708T>A	p.Trp570Arg	missense_variant	Exon 19 of 22		NP_001138908.1
LSS	NM_001145437.2 link	c.1501T>A	p.Trp501Arg	missense_variant	Exon 18 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 link	c.1741T>A	p.Trp581Arg	missense_variant	Exon 19 of 22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250614

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D;D

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

4.6

H;H;.;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-14

D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.99

MutPred

0.92

Gain of disorder (P = 0.0289);Gain of disorder (P = 0.0289);.;.;

MVP

0.81

MPC

1.3

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.95

gMVP

0.96

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over