rs879254498

chr19-11105276-C-Gchr19-11105276-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PM2 PM5 BP4_Moderate BP6_Moderate

The NM_000527.5(LDLR):c.370C>G(p.Arg124Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R124W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 0.0150

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 2 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251185.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21232066).
• BP6: Variant 19-11105276-C-G is Benign according to our data. Variant chr19-11105276-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 251184.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105276-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.370C>G	p.Arg124Gly	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.370C>G	p.Arg124Gly	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	11
Dann	Benign	0.58
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.61	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.0	N;N;N;N
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.040	B;.;.;.
Vest4		0.23
MutPred		0.53		Gain of glycosylation at S123 (P = 0.0746);Gain of glycosylation at S123 (P = 0.0746);.;Gain of glycosylation at S123 (P = 0.0746);
MVP		1.0
MPC		0.33
ClinPred		0.17	T
GERP RS		4.4
Varity_R		0.24
gMVP		0.88

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

Other links and lift over

dbSNP: rs879254498; hg19: chr19-11215952;