19-11120424-G-C

Position:

• chr19-11120424-G-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.2042G>C​(p.Cys681Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. C681G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.99

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 22 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 disulfide_bond (size 19) in uniprot entity LDLR_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) 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 chr19-11120423-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-11120424-G-C is Pathogenic according to our data. Variant chr19-11120424-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120424-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2042G>C	p.Cys681Ser	missense_variant	14/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2042G>C	p.Cys681Ser	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 29, 2024

PP3, PP4, PM1, PM2, PS3_supporting, PS4_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-9.4	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.92
MutPred		0.98		Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);.;.;Gain of disorder (P = 0.0245);
MVP		1.0
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs201637900; hg19: chr19-11231100;