19-11105549-C-A

Position:

• chr19-11105549-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.643C>A​(p.Arg215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.536

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 16 ACMG points.

• PM1: In a disulfide_bond (size 18) in uniprot entity LDLR_HUMAN there are 41 pathogenic changes around while only 2 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 chr19-11105549-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 19-11105549-C-A is Pathogenic according to our data. Variant chr19-11105549-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105549-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.643C>A	p.Arg215Ser	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.643C>A	p.Arg215Ser	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Benign	0.026
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	M;.;.;M
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.059	T;T;T;T
Sift4G	Benign	0.095	T;T;T;T
Polyphen		0.70	P;.;.;.
Vest4		0.46
MutPred		0.53		Gain of phosphorylation at R215 (P = 0.0778);Gain of phosphorylation at R215 (P = 0.0778);.;Gain of phosphorylation at R215 (P = 0.0778);
MVP		1.0
MPC		0.53
ClinPred		0.92	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs764042910; hg19: chr19-11216225;