Variant 19-11120488-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2106G>C (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003294 (0.0033%) in South Asian exomes (gnomAD v4.1.0). It is below 0.02%, so PM2 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA038621/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1B:1

Conservation

PhyloP100: 6.68

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2106G>C	p.Met702Ile	missense_variant	14/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2106G>C	p.Met702Ile	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250972

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135712

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461472

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Aug 30, 2024

The NM_000527.5(LDLR):c.2106G>C (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003294 (0.0033%) in South Asian exomes (gnomAD v4.1.0). It is below 0.02%, so PM2 is met. -

Familial hypercholesterolemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;.;.;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.64

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.0

M;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.038

D;T;D;D;D

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.049

B;.;.;.;.

Vest4

0.42

MutPred

0.54

Gain of catalytic residue at M702 (P = 0.0178);Gain of catalytic residue at M702 (P = 0.0178);.;.;Gain of catalytic residue at M702 (P = 0.0178);

MVP

1.0

MPC

0.29

ClinPred

0.84

GERP RS

4.1

Varity_R

0.62

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over