NM_000527.5:c.1236G>A

Variant names:

• chr19-11113327-G-A
• rs879254843
• NM_000527.5:c.1236G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 5P and 3B. PM1 PM5 PP2 BP4 BP6_Moderate

The NM_000527.5(LDLR):​c.1236G>A​(p.Met412Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M412L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.30
• Publications: 2 publications found

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11113325-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 440633.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29781598).
• BP6: Variant 19-11113327-G-A is Benign according to our data. Variant chr19-11113327-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 251746.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1236G>A	p.Met412Ile	missense	Exon 9 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1236G>A	p.Met412Ile	missense	Exon 9 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1113G>A	p.Met371Ile	missense	Exon 8 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1236G>A	p.Met412Ile	missense	Exon 9 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1494G>A	p.Met498Ile	missense	Exon 9 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1236G>A	p.Met412Ile	missense	Exon 9 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461590 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Benign	-0.84	N
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.51
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.25	B
Vest4		0.27
MutPred		0.44		Gain of methylation at K411 (P = 0.0245)
MVP		1.0
MPC		0.46
ClinPred		0.60	D
GERP RS		4.9
Varity_R		0.38
gMVP		0.81
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs879254843; hg19: chr19-11224003;