rs28931574
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000039.3(APOA1):c.148G>C(p.Gly50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G50S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000039.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.148G>C | p.Gly50Arg | missense_variant | 3/4 | ENST00000236850.5 | |
APOA1-AS | NR_126362.1 | n.123+814C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOA1 | ENST00000236850.5 | c.148G>C | p.Gly50Arg | missense_variant | 3/4 | 1 | NM_000039.3 | P1 | |
APOA1-AS | ENST00000669664.1 | n.74+814C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial amyloid polyneuropathy, Iowa type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1990 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APOA1 function (PMID: 17665932, 21296086, 22952757, 23233678, 27464946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOA1 protein function. ClinVar contains an entry for this variant (Variation ID: 17917). This variant is also known as glycine to arginine-26 substitution, ApoA-I Iowa, or G26R. This missense change has been observed in individual(s) with autosomal dominant systemic amyloidosis (PMID: 2123470). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 50 of the APOA1 protein (p.Gly50Arg). - |
Familial visceral amyloidosis, Ostertag type;C5551172:Hypoalphalipoproteinemia, primary, 2;C5677030:Hypoalphalipoproteinemia, primary, 2, intermediate Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 13, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at