2-21029968-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000384.3(APOB):āc.1400C>Gā(p.Ala467Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251374Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135846
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461694Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727158
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B Uncertain:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1Benign:1
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APOB-related disorder Uncertain:1
The APOB c.1400C>G variant is predicted to result in the amino acid substitution p.Ala467Gly. This variant was reported in 3 individuals diagnosed with familial hypercholesterolemia (Table 6, Razman AZ et al. 2022. PubMed ID: 36499307). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21252840-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 334172; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Familial hypobetalipoproteinemia 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiovascular phenotype Uncertain:1
The p.A467G variant (also known as c.1400C>G), located in coding exon 11 of the APOB gene, results from a C to G substitution at nucleotide position 1400. The alanine at codon 467 is replaced by glycine, an amino acid with similar properties. This variant has been detected in individuals with elevated LDL-C (Razman AZ et al. Int J Mol Sci, 2022 Nov;23; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at