chr19-11113584-A-G

Position:

• chr19-11113584-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The ENST00000558518.6(LDLR):​c.1408A>G​(p.Ser470Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S470C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.0390

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 uncertain in ENST00000558518.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11113584-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 664685.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 19-11113584-A-G is Pathogenic according to our data. Variant chr19-11113584-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369856.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36016366). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1408A>G	p.Ser470Gly	missense_variant	10/18	ENST00000558518.6	NP_000518.1
MIR6886	NR_106946.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1408A>G	p.Ser470Gly	missense_variant	10/18	1	NM_000527.5	ENSP00000454071	P3
MIR6886	ENST00000619864.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727176

Gnomad4 AFR exome AF: 0.0000299

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 Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Robarts Research Institute, Western University

-

- -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 470 of the LDLR protein (p.Ser470Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familiar hypercholesterolemia (PMID: 27765764; Invitae). ClinVar contains an entry for this variant (Variation ID: 369856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Ser470 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23130880; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	0.25
DANN	Benign	0.93
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.1	L;.;.;.;.;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.096
MutPred		0.44		Loss of glycosylation at S470 (P = 0.0328);Loss of glycosylation at S470 (P = 0.0328);.;.;.;Loss of glycosylation at S470 (P = 0.0328);
MVP		1.0
MPC		0.20
ClinPred		0.52	D
GERP RS		-1.9
Varity_R		0.28
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057516128; hg19: chr19-11224260;