rs149227065
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000384.3(APOB):āc.1061A>Gā(p.Glu354Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,176 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E354E) has been classified as Likely benign.
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.1061A>G | p.Glu354Gly | missense_variant | 9/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.1061A>G | p.Glu354Gly | missense_variant | 9/29 | 1 | NM_000384.3 | P1 | |
APOB | ENST00000399256.4 | c.1061A>G | p.Glu354Gly | missense_variant | 9/17 | 1 | |||
APOB | ENST00000673739.2 | c.*367A>G | 3_prime_UTR_variant, NMD_transcript_variant | 8/25 | |||||
APOB | ENST00000673882.2 | c.*367A>G | 3_prime_UTR_variant, NMD_transcript_variant | 8/23 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251442Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135886
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727242
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74468
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2024 | Variant summary: APOB c.1061A>G (p.Glu354Gly) results in a non-conservative amino acid change located in the Vitellogenin, N-terminal domain (IPR001747) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251442 control chromosomes (gnomAD). The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOB causing Early Onset Coronary Artery Disease phenotype (2e-05). To our knowledge, no occurrence of c.1061A>G in individuals affected with Early Onset Coronary Artery Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 334175). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hypercholesterolemia, autosomal dominant, type B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
APOB-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 31, 2022 | The APOB c.1061A>G variant is predicted to result in the amino acid substitution p.Glu354Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21256234-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hypercholesterolemia, familial, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 04, 2019 | - - |
Familial hypobetalipoproteinemia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2021 | The p.E354G variant (also known as c.1061A>G), located in coding exon 9 of the APOB gene, results from an A to G substitution at nucleotide position 1061. The glutamic acid at codon 354 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at