rs138929605
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5
The NM_002693.3(POLG):c.830A>T(p.His277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,614,118 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_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000378 AC: 95AN: 251244Hom.: 0 AF XY: 0.000368 AC XY: 50AN XY: 135816
GnomAD4 exome AF: 0.000694 AC: 1015AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.000652 AC XY: 474AN XY: 727212
GnomAD4 genome AF: 0.000348 AC: 53AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27AN XY: 74502
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:6
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PM3, PP1 -
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The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 26095671) In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. -
POLG: PM3:Very Strong, PM2 -
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25203713, 21301859, 22357363, 27987238, 30609409, 24508722, 22114710, 28337550, 21880868, 26095671, 27538604, 24642831, 32347949, 18487244, Spoljaric2023[paper], 35114397, 31440721, 22000311, 30451971, 38294884, 33791913) -
Progressive sclerosing poliodystrophy Pathogenic:3
This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 277 of the POLG protein (p.His277Leu). This variant is present in population databases (rs138929605, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 18487244, 21301859, 22357363). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLG protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 22114710, 24508722, 26095671, 27987238). For these reasons, this variant has been classified as Pathogenic. -
The NM_002693.2:c.830A>T (NP_002684.1:p.His277Leu) [GRCH38: NC_000015.10:g.89330106T>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic. -
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Mitochondrial DNA depletion syndrome Pathogenic:1
The p.His277Leu variant in POLG has been previously reported in one child with A lpers syndrome (Ashley 2008), one patient with progressive external ophthalmople gia and parkinsonism (Sato 2011), one patient with mitochondrial DNA depletion s yndrome presenting as sensory ataxic neuropathy with cerebellar features (McKelv ie 2012). All three patients were compound heterozygotes. This variant has been identified in 48/121174 of chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs138929605). Although this variant has been seen in the general population, its frequency is low enough to be consisten t with a recessive carrier frequency. Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.His277Leu variant is likely pathogenic. -
Tip-toe gait Pathogenic:1
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
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Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
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not specified Uncertain:1
Variant summary: POLG c.830A>T (p.His277Leu) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251244 control chromosomes, predominantly at a frequency of 0.00071 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 dataset). However, within certain European subpopulations the variant is reported with an even higher allele frequency, e.g. in the Swedish, with an allele frequency of 0.0015. This frequency is not higher than the estimated maximum expected for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (0.0035), allowing no clear conclusion about variant significance. c.830A>T has been reported in the literature as a compound heterozygous genotype in individuals affected with POLG-Related Spectrum Disorders, including Alpers syndrome and progressive external ophthalmoplegia (PEO) (e.g. Ashley_2008, Sato_2011, McKelvie_2012). In addition, it has also been reported as a complex allele (i.e. in cis) with another (potentially) pathogenic POLG variant (p.R232H) in at least 4 individuals, who were affected with infantile hepatopathy (Hunter_2011) or Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO) (Bereau_2016); all of these individuals carried a (likely) pathogenic variant in trans. These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, one showing no damaging effect of this variant in its ability to bind and synthesize DNA and in its exonuclease and strand displacement activity (Macao_2015), while another demonstrating partially reduced exonuclease activity (Kasahara_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18487244, 22000311, 33791913, 26095671, 35114397, 22357363, 30451971, 21301859, 27987238, 27538604, 38294884). ClinVar contains an entry for this variant (Variation ID: 206583). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
POLG-Related Spectrum Disorders Uncertain:1
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Inborn genetic diseases Uncertain:1
The c.830A>T (p.H277L) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a A to T substitution at nucleotide position 830, causing the histidine (H) at amino acid position 277 to be replaced by a leucine (L). The in silico prediction for the p.H277L alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hereditary spastic paraplegia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at