19-11105582-T-A

Position:

• chr19-11105582-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000527.5(LDLR):​c.676T>A​(p.Ser226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S226F) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84

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 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 chr19-11105583-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.676T>A	p.Ser226Thr	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.676T>A	p.Ser226Thr	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151920 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151920 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74214

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Benign	0.072	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.65
MutPred		0.84		Gain of phosphorylation at S226 (P = 0.1086);Gain of phosphorylation at S226 (P = 0.1086);.;Gain of phosphorylation at S226 (P = 0.1086);
MVP		1.0
MPC		0.77
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.65
gMVP		0.97

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: rs879254635; hg19: chr19-11216258;