chr19-11113280-T-C

Position:

• chr19-11113280-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000527.5(LDLR):​c.1189T>C​(p.Ser397Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S397F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19393814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1189T>C	p.Ser397Pro	missense_variant, splice_region_variant	9/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1189T>C	p.Ser397Pro	missense_variant, splice_region_variant	9/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460444 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726532

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.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 23, 2019

This missense variant (also known as p.Ser376Pro in the mature protein) replaces serine with proline at codon 397 of the LDLR protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.15	N;.;.;.;.;N
MutationTaster	Benign	0.75	D;D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.037	D;T;T;D;T;D
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.12
MutPred		0.60		Loss of catalytic residue at S397 (P = 0.0281);Loss of catalytic residue at S397 (P = 0.0281);.;.;.;Loss of catalytic residue at S397 (P = 0.0281);
MVP		1.0
MPC		0.27
ClinPred		0.14	T
GERP RS		2.8
Varity_R		0.36
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs879254825; hg19: chr19-11223956;