19-11100303-G-T

Variant names:

• chr19-11100303-G-T
• rs137853960
• NM_000527.5:c.148G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023515/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:7 B:19 O:1
• Conservation: PhyloP100: -0.218
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.148G>T	p.Ala50Ser	missense	Exon 2 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.148G>T	p.Ala50Ser	missense	Exon 2 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.148G>T	p.Ala50Ser	missense	Exon 2 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.148G>T	p.Ala50Ser	missense	Exon 2 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.406G>T	p.Ala136Ser	missense	Exon 2 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.148G>T	p.Ala50Ser	missense	Exon 2 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000530 AC: 133 AN: 251180 AF XY: 0.000538

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000632 AC: 923 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 434 AN XY: 727038

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000773 AC: 859 AN: 1111886

Other (OTH) AF: 0.000348 AC: 21 AN: 60394

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74450

African (AFR) AF: 0.000144 AC: 6 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	10	Hypercholesterolemia, familial, 1 (14)
-	1	3	not specified (4)
-	1	2	not provided (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypercholesterolemia (1)
-	-	1	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	0.058
DANN	Benign	0.83
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.047	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.77	N
PhyloP100		-0.22
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.55
Sift	Benign	0.32	T
Sift4G	Benign	0.49	T
Polyphen		0.014	B
Vest4		0.12
MVP		1.0
MPC		0.23
ClinPred		0.010	T
GERP RS		-5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.098
gMVP		0.83
Mutation Taster		=85/15	polymorphism

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: rs137853960; hg19: chr19-11210979;