rs879255170

chr19-11123327-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000527.5(LDLR):c.2294T>G(p.Val765Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V765A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.537

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39921418).
• BP6: Variant 19-11123327-T-G is Benign according to our data. Variant chr19-11123327-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 252266.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11123327-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2294T>G	p.Val765Gly	missense_variant	15/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2294T>G	p.Val765Gly	missense_variant	15/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251110 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135790

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: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727210

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	10
Dann	Benign	0.85
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.47	T;T;T;T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		0.31	B;.;.;.;.;.
Vest4		0.38
MutPred		0.54		Loss of stability (P = 0.0072);Loss of stability (P = 0.0072);.;.;.;Loss of stability (P = 0.0072);
MVP		1.0
MPC		0.28
ClinPred		0.055	T
GERP RS		2.1
Varity_R		0.12
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879255170; hg19: chr19-11234003;