19-11102786-C-G

Variant names:

• chr19-11102786-C-G
• NM_000527.5:c.313C>G

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.313C>G​(p.Pro105Ala) 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 1,460,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P105S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Scores: Splicing: ADA: 0.00005776
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29

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 domain LDL-receptor class A 2 (size 40) in uniprot entity LDLR_HUMAN there are 46 pathogenic changes around while only 6 benign (88%) in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07247466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.313C>G	p.Pro105Ala	missense_variant, splice_region_variant	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.313C>G	p.Pro105Ala	missense_variant, splice_region_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460910 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.0050
DANN	Benign	0.62
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.11	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.75	T
PROVEAN	Benign	1.8	N
REVEL	Uncertain	0.55
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.15
MutPred		0.43		Loss of catalytic residue at L105 (P = 0.0556);
MVP		0.80
ClinPred		0.036	T
GERP RS		-11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.15
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11213462;