19-11123239-G-C

Variant names:

• chr19-11123239-G-C
• rs547268730
• NM_000527.5:c.2206G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000527.5(LDLR):​c.2206G>C​(p.Val736Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V736I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1768584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2206G>C	p.Val736Leu	missense_variant	Exon 15 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2206G>C	p.Val736Leu	missense_variant	Exon 15 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74290

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000178 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.0050
DANN	Benign	0.51
DEOGEN2	Benign	0.39	T;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.23	T;T;T;T;T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L;.;.;.;.;L
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.76	N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.76	T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Polyphen		0.012	B;.;.;.;.;.
Vest4		0.064
MutPred		0.24		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;.;Loss of sheet (P = 0.0315);
MVP		0.87
MPC		0.21
ClinPred		0.065	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.66

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

Other links and lift over

dbSNP: rs547268730; hg19: chr19-11233915;