NM_000384.3:c.3491G>C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000384.3(APOB):c.3491G>C(p.Arg1164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
ACMG classification criteria: PS3, PM2 -
0/176 non-FH alleles -
- -
not specified Uncertain:1
- -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on binding and internalization of LDL (Alves et al., 2014); This variant is associated with the following publications: (PMID: 26643808, 26020417, 24234650, 32719484) -
Cardiovascular phenotype Uncertain:1
The p.R1164T variant (also known as c.3491G>C), located in coding exon 22 of the APOB gene, results from a G to C substitution at nucleotide position 3491. The arginine at codon 1164 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals with features consistent with familial hypercholesterolemia (FH) (Alves AC et al. Hum Mol Genet, 2014 Apr;23:1817-28; Ambry internal data). In assays testing APOB function, this variant showed functionally abnormal results (Alves AC et al. Hum Mol Genet, 2014 Apr;23:1817-28; Fernández-Higuero JA et al. Sci Rep, 2015 Dec;5:18184). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant is unclear for autosomal dominant familial hypercholesterolemia; however, it is unlikely to be causative of autosomal recessive hypobetalipoproteinemia. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at