19-11131982-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):c.*666T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 187,572 control chromosomes in the GnomAD database, including 43,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34364 hom., cov: 28)
  • Exomes 𝑓: 0.71 (9306 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310

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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-11131982-T-C is Benign according to our data. Variant chr19-11131982-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.*666T>C		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*666T>C		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100191 AN: 151614 Hom.: 34352 Cov.: 28

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.672

GnomAD4 exome AF: 0.710 AC: 25460 AN: 35840 Hom.: 9306 Cov.: 0 AF XY: 0.707 AC XY: 13360 AN XY: 18894

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.808

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.654

Gnomad4 FIN exome AF: 0.706

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.661 AC: 100251 AN: 151732 Hom.: 34364 Cov.: 28 AF XY: 0.664 AC XY: 49202 AN XY: 74146

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.783

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.721

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.744

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.669

Alfa AF: 0.718 Hom.: 54374

Bravo AF: 0.657

Asia WGS AF: 0.680 AC: 2363 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jul 21, 2017	Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.6
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1433099; hg19: chr19-11242658; COSMIC: COSV52945335; COSMIC: COSV52945335;