19-11128085-G-C

Position:

• chr19-11128085-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The ENST00000558518.6(LDLR):​c.2389G>C​(p.Val797Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V797M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR ENST00000558518.6 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.41

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 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 chr19-11128085-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 19-11128085-G-C is Pathogenic according to our data. Variant chr19-11128085-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565983.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2389G>C	p.Val797Leu	missense_variant, splice_region_variant	16/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2389G>C	p.Val797Leu	missense_variant, splice_region_variant	16/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2018

The c.2389G>C variant (also known as p.V797L), located in coding exon 16 of the LDLR gene, results from a G to C substitution at nucleotide position 2389. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the valine at codon 797 to leucine, an amino acid with highly similar properties. Two disease-causing mutations, c.2389G>A p.V797M and c.2389G>T p.V797L, have been described at the same nucleotide position (Pereira E et al. Hum. Genet. 1995;96:319-22; Lombardi MP et al. Clin. Genet. 2000;57:116-24). An impact on splicing has been demonstrated for the c.2389G>T mutation, which causes exon 16 skipping and is predicted to result in an in-frame deletion of 26 amino acids (p.A771_I796del) in the extracellular and the trans-membrane domains of the LDLR protein (Bourbon M et al. J. Med. Genet. 2009;46:352-7). This nucleotide position is highly conserved in available vertebrate species, but the amino acid position is poorly conserved. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2018

This sequence change replaces valine with leucine at codon 797 of the LDLR protein (p.Val797Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 16 of the LDLR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). 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. Variants that disrupt the c.2389G nucleotide in LDLR have been observed in affected individuals (PMID: 10735632, 18325082, 19411563, 23375686, 19446849, 22698793, 22859806, 20145306, 9763532). This suggests that it is a clinically significant nucleotide, and that other variants that disrupt this residue are likely to be causative of disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with hypercholesterolemia (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.71
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.44	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-1.1	N
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.020	D
Vest4		0.32
MVP		0.91
ClinPred		0.19	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750518671; hg19: chr19-11238761;