19-11105270-A-G

Variant names:

• chr19-11105270-A-G
• rs879254493
• NM_000527.5:c.364A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The ENST00000558518.6(LDLR):​c.364A>G​(p.Ile122Val) 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 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I122L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.602
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 14 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 chr19-11105270-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 251178.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558518.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.364A>G	p.Ile122Val	missense	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.364A>G	p.Ile122Val	missense	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.241A>G	p.Ile81Val	missense	Exon 3 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.364A>G	p.Ile122Val	missense	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.622A>G	p.Ile208Val	missense	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.364A>G	p.Ile122Val	missense	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461392 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	5.5
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.60
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.40
Sift	Benign	0.16	T
Sift4G	Benign	0.29	T
Polyphen		0.37	B
Vest4		0.10
MutPred		0.81		Loss of catalytic residue at I122 (P = 0.116)
MVP		0.92
MPC		0.24
ClinPred		0.27	T
GERP RS		2.2
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.90
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs879254493; hg19: chr19-11215946;