rs1060501102
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_014585.6(SLC40A1):c.1469G>A(p.Gly490Asp) variant causes a missense change involving the alteration of a 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. G490S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014585.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC40A1 | NM_014585.6 | c.1469G>A | p.Gly490Asp | missense_variant | 8/8 | ENST00000261024.7 | |
SLC40A1 | XM_047444066.1 | c.1349G>A | p.Gly450Asp | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC40A1 | ENST00000261024.7 | c.1469G>A | p.Gly490Asp | missense_variant | 8/8 | 1 | NM_014585.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hemochromatosis type 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 12, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC40A1 function (PMID: 15692071, 15956209, 24714983). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 406376). This missense change has been observed in individuals with hyperferritinemia and iron overload (PMID: 12873829, 21199650, 24714983). 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 aspartic acid, which is acidic and polar, at codon 490 of the SLC40A1 protein (p.Gly490Asp). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics and Genomics, Rennes University Hospital | Jul 01, 2020 | Identified in 11 patients harbouring clinical and biochemical symptomes of type 4 haemochromatosis - |
SLC40A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 12, 2024 | The SLC40A1 c.1469G>A variant is predicted to result in the amino acid substitution p.Gly490Asp. This variant was reported in patients with hemochromatosis type 4 (Jouanelle et al. 2003. PubMed ID: 12873829; Rice et al. 2009. PubMed ID: 19150361; Le Gac et al. 2013. PubMed ID: 23784628; Callebaut et al. 2014. PubMed ID: 24714983). An in vitro study showed that this variant caused a loss of iron export function (Schimanski et al. 2005. PubMed ID: 15692071). Of note, another missense variant affecting the same amino acid (p.Gly490Ser) has also been reported as causative for hyperferritinemia (Callebaut et al. 2014. PubMed ID: 24714983). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/406376/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at