19-11120188-T-G

Position:

chr19-11120188-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala) variant is classified as Uncertain significance - insufficient evidencefor Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) variant is exonic and there is no GT nearbyVariant is not predicted to alter splicing.--- BP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404093067/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:5

Conservation

PhyloP100: 1.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

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

BP4

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.1942T>G	p.Ser648Ala	missense_variant	13/18	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.1942T>G	p.Ser648Ala	missense_variant	13/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces serine with alanine at codon 648 in the LDLR type B repeat 6 EGF precursor homology domain of the LDLR protein. This variant is also known as p.Ser627Ala in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with maximum total cholesterol level of 251 mg/dL (PMID: 32009526). This variant has been identified in 4/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ser648Pro, is reported to cause disease (ClinVar variation ID: 252120), indicating that serine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 27, 2023	The NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala) variant is classified as Uncertain significance - insufficient evidencefor Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1), so PM2 is met. BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) variant is exonic and there is no GT nearby Variant is not predicted to alter splicing. --- BP4 is Met. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 12, 2022	The c.1942T>G variant in LDLR has previously been reported in an individual with hypercholesterolemia [PMID: 32009526] and it has been deposited in ClinVar[ClinVar ID: 431538]. The c.1942T>G variant is observed in 12 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1and v3.1.2, TOPMed Freeze 8), suggesting+AO16 it is not a common benign variant in the populations represented in those databases. The c.1942T>G variant in LDLR islocated in exon 13 of this 18-exon gene, and is predicted to replace an evolutionarily moderately conserved serine amino acid with alanine at position 648(p.(Ser648Ala)) in the LDL-receptor class B6 (YWTD-6) repeat in the extracellular domain of the encoded protein. In silico predictions are not supporting a damagingeffect for the p.(Ser648Ala) variant [CADD v1.6 = 17.5, REVEL = 0.487]; however, there are no functional studies to support or refute these predictions. Variants at the same codon (p.(Ser648Pro) and p.(Ser648Phe)) have been reported in the literature in individuals with hypercholesterolemia [PMID: 17765246] and deposited inClinVar [ClinVar ID: 252120 and 440670]. Based on available evidence this c.1942T>G p.(Ser648Ala) variant identified in LDLR is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 02, 2024

BP4, PM2, PM5 -

Familial hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 06, 2023

This missense variant replaces serine with alanine at codon 648 in the LDLR type B repeat 6 EGF precursor homology domain of the LDLR protein. This variant is also known as p.Ser627Ala in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with maximum total cholesterol level of 251 mg/dL (PMID: 32009526). This variant has been identified in 4/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ser648Pro, is reported to cause disease (ClinVar variation ID: 252120), indicating that serine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.78

D;.;.;.;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.65

T;T;T;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.45

T;T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.8

M;.;.;.;.;M

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.22

T;T;T;T;T;T

Sift4G

Benign

0.38

T;T;T;T;T;T

Polyphen

0.032

B;.;.;.;.;.

Vest4

0.40

MutPred

0.51

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;.;Loss of helix (P = 0.1299);

MVP

0.99

MPC

0.42

ClinPred

0.77

GERP RS

4.3

Varity_R

0.66

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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