chr19-11105527-C-T

Variant names:

• chr19-11105527-C-T
• rs121908044
• NM_000527.5:c.621C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.621C>T​(p.Gly207Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,344 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 pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -0.962

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11105527-C-T is Pathogenic according to our data. Variant chr19-11105527-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105527-C-T is described in Lovd as [Pathogenic]. Variant chr19-11105527-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.621C>T	p.Gly207Gly	synonymous_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.621C>T	p.Gly207Gly	synonymous_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461344 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726976

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: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:9

Sep 01, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 5, family member = 1 -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 22, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly207Gly variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in numerous affected individuals from several families; of note, at least 2 of these individuals were homozygous and displayed features of autosomal recessive FH (Defesche 2008 PMID: 18400033, Durst 2017 PMID: 28104544, Martín-Campos 2018 PMID: 30293936). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 3747) and was absent from large population studies. Computational tools predict a splicing impact and an in vitro analyses supported an alteration of splicing leading to an in-frame deletion of 75 bp (Defesche 2008 PMID: 18400033, Martin-Campos 2018 PMID: 30293936). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PS4, PM2_Supporting, PP1_Strong, PS3_Supporting, PM3. -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to be one of the most common LDLR variants in FH patients from the Netherlands (Defesche et al., 2008; Kusters et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Published functional studies demonstrate a damaging effect with abnormal gene splicing resulting in the in-frame deletion of 25 amino acids affecting the LDL-receptor class A5 domain (Defesche et al., 2008); Also known as G186=; This variant is associated with the following publications: (PMID: 22390909, 27821657, 18400033, 28104544, 32977124, 30293936, 33740630, 34037665, 21475731) -

Cardiovascular phenotype Pathogenic:1

Dec 23, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.621C>T pathogenic mutation (also known as p.G207G), located in coding exon 4, results from a C to T substitution at nucleotide position 621 of the LDLR gene. This nucleotide substitution does not change the amino acid at codon 207. This mutation has been reported in several familial hypercholesterolemia cohorts, and in one of the studies, the average LDL-C level in family members positive for the mutation was elevated compared with relatives who did not carry the alteration (Defesche JC et al. Clin. Genet. 2008;73:573-8; Kusters DM et al. Neth Heart J. 2011;19:175-182; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9:504-510; Durst R et al. Atherosclerosis. 2017;257:55-63). In addition, this mutation has been identified in the homozygous state in two unrelated individuals with LDL-C levels indicative of homozygous familial hypercholesterolemia, both of whom suffered myocardial infarction at a young age (Defesche JC et al. Clin. Genet. 2008;73:573-8). RNA studies indicate that the variant creates a cryptic donor splice site in coding exon 4 and results in the in-frame deletion of 25 amino acids in LDL type A repeat 5, which is important for ligand binding (Defesche JC et al. Clin. Genet. 2008;73:573-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 207 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 18400033, 28104544, 30293936). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 3747). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 18400033). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Glu208Lys) have been determined to be pathogenic (PMID: 1301956, 18677035, 22390909). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908044; hg19: chr19-11216203; COSMIC: COSV52944419; COSMIC: COSV52944419;