rs1131691575
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_002693.3(POLG):c.3550G>A(p.Asp1184Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1184G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002693.3 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 |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3550G>A | p.Asp1184Asn | missense_variant | 22/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2822G>A | 3_prime_UTR_variant | 22/23 | |||
POLG | NM_001126131.2 | c.3550G>A | p.Asp1184Asn | missense_variant | 22/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3550G>A | p.Asp1184Asn | missense_variant | 22/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Apr 07, 2017 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | May 23, 2021 | The c.3550 G>A (p.Asp1184Asn) variant in POLG has been reported in gnomAD in 0.0001% allele frequency with no homozygotes (PM2). There is also multiple other pathogenic variants at the same amino acid residue as well as nearby: Asp1184His, Ile1185Thr, Ile1185Asn, Asp1186His, and Cys1188Arg all have been reported in the Human Gene Mutation Database in association with POLG-related disorders (PS1; PMID 24077912). There are 5 cases reported with POLG related disease symptoms PEO, neurological phenotype, liver issues, and epilepsy. These cases are reported in 2 compound heterozygotes with c.679 C>T; p.Arg227Trp, a compound heterozygote with c.752 C>T; p.Thr251Ile and c.1759 C>T; p.Pro587Leu; a compound heterozygote with c.3285 C>G; p.Ser1095Arg (PM3_strong; PMID:16957900; PMID:30678510; PMID:19344718; PMID:19578034).There is 1 additional case in the literature as a compound heterozygotes however there is conflicting evidence of pathogenicity of the variant. Therefore this case could not be counted (PMID: 16401742). In summary, this variant meets criteria to be classified as pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PS1, PM2, PM3_strong - |
Progressive sclerosing poliodystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2023 | ClinVar contains an entry for this variant (Variation ID: 426100). This missense change has been observed in individuals with autosomal recessive POLG-related disorders (PMID: 16401742, 16957900, 19578034, 30678510). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1184 of the POLG protein (p.Asp1184Asn). 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 POLG protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 06, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2021 | The c.3550G>A (p.D1184N) alteration is located in exon 22 (coding exon 21) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 3550, causing the aspartic acid (D) at amino acid position 1184 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the POLG c.3550G>A alteration was observed in 0.001% (3/282,882) of total alleles studied, with a frequency of 0.003% (1/35,440) in the Latino subpopulation. This alteration has been previously reported in multiple patients with autosomal recessive POLG-related mitochondrial disorders, including progressive external ophthalmoplegia (arPEO) (Gonzalez-Vioque, 2006; de Vries, 2007; Blok, 2009; Li, 2019). This amino acid position is highly conserved in available vertebrate species. Functional studies using yeast mtDNA point mutagenesis with p.D1184N (yeast ortholog D941N) showed an increased petite colony formation frequency and exhibited decreased mtDNA copy number, suggesting that mtDNA depletion is a major phenotype of this disease-associated mutant (Stumpf, 2010). The in silico prediction for the p.D1184N alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2018 | The D1184N variant in the POLG gene has been reported previously in multiple unrelated individuals with POLG-related disorders who had a second POLG variant identified (de Vries et al., 2007; Amiot et al., 2009; Blok et al., 2009). Functional studies show that D1184N results in mtDNA depletion as well as increased petite colony formation, suggesting it may be a null variant (Stumpf et al., 2010). The D1184N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1184N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and a different missense variant in the same residue (D1184H) as well as missense variants in nearby residues (I1185T, I1185N, D1186H, C1188R) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, D1184N is considered a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at