rs879254758

Positions:

• chr19-11110730-GC-TG

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1019_1020delGCinsTG​(p.Cys340Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C340W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.65

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]

LDLR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain EGF-like 1 (size 39) in uniprot entity LDLR_HUMAN there are 56 pathogenic changes around while only 3 benign (95%) 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 chr19-11110731-C-G is described in Lovd as [Likely_pathogenic].
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-11110730-GC-TG is Pathogenic according to our data. Variant chr19-11110730-GC-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1019_1020delGCinsTG	p.Cys340Leu	missense_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1019_1020delGCinsTG	p.Cys340Leu	missense_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	Index case (homozygote) = 1 , family members = 5 with co-segregation (2 homozygotes in the family) -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 08, 2019

The p.Cys340Leu variant in LDLR has been reported in at least 3 individuals with familial hypercholesterolemia (FH): One in the heterozygous state (Marduel 2010) and two in the homozygous state (where at least one of these individuals was from a consanguineous family) and segregated with disease in more than 6 heterozygous affected family members from 2 families (Ahmed 2013, ClinVar; submission accession: SCV000503280.1). It has also been identified in 0.007% (2/30614) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Three additional variants at this codon have been reported in individuals with FH (p.Cys340Phe, p.Cys340Trp and p.Cys340Tyr), suggesting variation at this position may not be tolerated (Stenson 2017). Computational prediction tools and conservation analysis suggest that the p.Cys340Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2; PP1_Moderate; PP3; PM3_Supporting. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.1019_1020delGCinsTG variant (also known as p.C340L), located in coding exon 7 of the LDLR gene, results from an in-frame deletion of GC and insertion of TG at nucleotide positions 1019 to 1020. This results in the substitution of the cysteine residue for a leucine residue at codon 340, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). This variant has been detected in the heterozygous state and homozygous state in individuals with features consistent with heterozygous and homozygous FH (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Orsoni A et al. J Lipid Res, 2011 Dec;52:2304-2313; Ahmed W et al. Clin Chim Acta, 2013 Jun;421:219-25; Ambry internal data). Another variant at the same codon, p.C340Y (c.1019G>A), has been been reported in association with FH (Mozas P et al. Hum Mutat, 2004 Aug;24:187). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 251599). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 23535506). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.08%). This sequence change replaces cysteine, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 340 of the LDLR protein (p.Cys340Leu). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254758; hg19: chr19-11221406;