19-11107494-A-G

Variant names:

• chr19-11107494-A-G
• rs1555803908
• NM_000527.5:c.920A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM3 PS4_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP3, PP4, and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and homozygous for the NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant (PMID:28502510). PP3: REVEL = 0.985. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine). PS4_Supporting: Variant meets PM2 and is identified in at least three index cases who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (PMID:28502510, M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine). LINK:https://erepo.genome.network/evrepo/ui/classification/CA404081052/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.21

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.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.920A>G	p.Asp307Gly	missense_variant	Exon 6 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.920A>G	p.Asp307Gly	missense_variant	Exon 6 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456926 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Jun 28, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.920A>G (p.Asp307Gly) missense variant lies in one of the ligand-binding domains. This variant has been reported in at least four unrelated individuals with familial hypercholesterolemia (PMID: 19717150; 30710474; 34037665; 34456049). The p.Asp307Gly variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Several other missense changes at the same amino acid residue have been reported in ClinVar and the literature in individuals with familial hypercholesterolemia (PMID: 21310417; 32706999). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.920A>G (p.Asp307Gly) variant is classified as likely pathogenic for familial hypercholesterolemia. -

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Sep 27, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19717150, 18096825, 28502510, 34037665, 30710474, 30293936, 34456049) -

Dec 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3, PM5, PS4_moderate -

Familial hypercholesterolemia Pathogenic:2

Jul 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.920A>G (p.Asp307Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251216 control chromosomes (gnomAD). c.920A>G has been reported in the literature in many heterozygous individuals affected with Familial Hypercholesterolemia (FH; e.g., Junyent_2008, Junyent_2010, Martin-Campos_2018, DiTaranto_2019, Sturm_2021, Marco-Benedi_2022, Zhan_2023 (preprint, no PMID)), as well as compound heterozygous and homozygous individuals affected with FH (e.g., Banaras_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28502510, 30710474, 18096825, 19717150, 34456049, 30293936, 34037665). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Additionally, several different missense variants affecting the same codon, namely p.Asp307Asn, p.Asp307Glu, p.Asp307Ala, and p.Asp307His have all been reported in the literature in patients affected with familial hypercholesterolemia (PMIDs: 21310417, 33027386, 28965616, 12436241, 17094996). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 307 of the LDLR protein (p.Asp307Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 19717150, 28502510, 30710474, 34037665). This variant is also known as Asp286Gly (D286G). ClinVar contains an entry for this variant (Variation ID: 523725). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Asp307 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 17094996, 28965616), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	5.1	H;.;.;.;.;H
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.88
MutPred		0.94		Gain of ubiquitination at K311 (P = 0.1215);Gain of ubiquitination at K311 (P = 0.1215);.;.;.;Gain of ubiquitination at K311 (P = 0.1215);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1555803908; hg19: chr19-11218170;