rs113994096

chr15-89325639-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

The NM_002693.3(POLG):c.1760C>T(p.Pro587Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,612,514 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. P587P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:43 U:5 O:2
• Conservation: PhyloP100: 10.0

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLGARF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002693.3
• PP5: Variant 15-89325639-G-A is Pathogenic according to our data. Variant chr15-89325639-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13505.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=24, Uncertain_significance=5, Likely_pathogenic=10, not_provided=2}. Variant chr15-89325639-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.090871036).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1760C>T	p.Pro587Leu	missense_variant	10/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1032C>T		3_prime_UTR_variant	10/23
POLG	NM_001126131.2	c.1760C>T	p.Pro587Leu	missense_variant	10/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1760C>T	p.Pro587Leu	missense_variant	10/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00155 AC: 386 AN: 249778 Hom.: 1 AF XY: 0.00158 AC XY: 214 AN XY: 135208

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000344

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00203 AC: 2969 AN: 1460200 Hom.: 2 Cov.: 33 AF XY: 0.00197 AC XY: 1433 AN XY: 726516

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.000521

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74476

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.00157

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00170 AC: 206

EpiCase AF: 0.00256

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:43 Uncertain:5 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:14 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2023	PP3, PM2, PS3_moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2019	This variant is seen in cis with POLG c.752C>T (p.Thr251Ile), and the pathogenicity assessment is based on data for NM_002693.2:c.752C>T(;)1760C>T. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2023	- -

Progressive sclerosing poliodystrophy Pathogenic:5 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 28, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. These two variants have been previously reported as pathogenic and are frequently in cis configuration [PMID 12210792, 19189930, 23665194, 28154168, 22616202, 25585994, 23783014, 26468652, 19566497, 20513108, 24122062] -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 10, 2019	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Dec 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (rs113994096, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Thr251Ile) variant (PMID: 12210792, 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. To date, the p.Pro587Leu variant has not been observed independent from the p.Thr251Ile variant in individuals with autosomal recessive POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 13505). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, because it almost always occurs in cis with p.Thr251Ile, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. 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 Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2022	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jul 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013505). The variant was observed in cis with NM_002693.3:c.752C>T (p.Thr251Ile) in many individuals affected with POLG-related diseases (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -

POLG-related disorder Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 17, 2021	The POLG c.1760C>T p.(Pro587Leu) missense variant is well described in the literature and has been reported in individuals with a phenotype consistent with POLG-related spectrum disorders (Van Goethem et al., 2003; Filosto et al. 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013; Uusimaa et al. 2013). In almost all of the reported cases, the p.Pro587Leu variant was found in cis with p.Thr251Ile as the complex allele [p.Thr251Ile; p.Pro587Leu]. In an additional two individuals, the p.Pro587Leu variant was found as part of a complex allele with a p.Pro589Leu variant. The p.Pro587Leu variant has also been reported independently in three individuals from the same family in a heterozygous state displaying a dominant pattern of inheritance. Euro et al. (2011) assessed the structure-function relationships of variants in the POLG gene and reported that the p.Pro587Leu variant constrains the Beta-hairpin loop between the IP and AID subdomains and postulate it likely reduces processivity as a result of misalignment of the ptDNA with respect to the catalytic site. DeBalsi et al. (2017) investigated the biochemical properties of purified recombinant Pol gamma p.Pro587Leu protein expressed using the baculovirus Sf9 system. Experiments demonstrated that the p.Pro587Leu variant caused a two-fold reduction in DNA binding affinity and significantly reduced thermostability. The catalytic efficiency of the p.Pro587Leu protein was reduced to approximately 32% of the wildtype level. The [p.Thr251Ile; p.Pro587Leu] variant protein demonstrated a more severe catalytic dysfunction, retaining 5% activity compared to the wild type protein and suggesting that these two variants have a synergistic effect. Based on the collective evidence the p.Pro587Leu variant is classified as pathogenic when found as part of a complex allele and of uncertain significance when found independently. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 02, 2022	PS3, PM3_Strong, PP1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 19, 2022	_x000D_Criteria applied: PS3, PS4_SUP, PP3, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; 25660390; 12975295; 1539879; 19578034; 24265579; 23448099;25742477; 26224072) - PS4.The p.(Pro587Leu) was detected in trans with a pathogenic variant (PMID: 19578034) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 25660390) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Mitochondrial DNA depletion syndrome 4b Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 27, 2021	Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 13, 2021	A heterozygous missense variation in exon 10 of the POLG gene that results in the amino acid substitution of Leucine for Proline at codon587 was detected. The observed variant c.1760C>T (p.Pro587Leu) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 05, 2023	The POLG c.1760C>T variant is classified as LIKELY PATHOGENIC (PS3, PS4_moderate, PP1_moderate, PP3) This sequence change in exon 10 of 23 replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (gnomAD 232/152196 heterozygotes, 0 homozygote). The variant has been reported in dbSNP (rs113994096). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13505). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it has been observed on the same chromosome (in cis) with the second (p.Thr251Ile) variant also detected in this patient (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868) (PS4_moderate). In many of these previously reported cases, the two variants in cis were observed on the opposite chromosome (in trans) from a third, pathogenic variant in an affected individual. The p.Pro587Leu and p.Thr251Ile variant combination in cis accounts for approximately 6% of disease-causing alleles in POLG-related disorders, mainly in Caucasians (PMID: 21880868). The p.Pro587Leu and Thr251Ile variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879) (PP1_moderate). Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3). NO THIRD POLG variant was detected in this patient -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 15, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Mitochondrial disease Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	Apr 07, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1760C>T (p.P587L) alteration is located in exon 10 (coding exon 9) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 1760, causing the proline (P) at amino acid position 587 to be replaced by a leucine (L). Based on the available evidence, the c.1760C>T (p.P587L) alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant progressive external ophthalmoplegia. Based on data from the Genome Aggregation Database (gnomAD), the POLG c.1760C>T alteration was observed in 0.15% (433/281158) of total alleles studied, with a frequency of 0.26% (341/128840) in the European (non-Finnish) subpopulation. This mutation has been reported to occur almost exclusively in cis with p.T251I (c.752C>T) and this syntenic mutation combination accounts for approximately 6% of all disease causing alleles in POLG (Tang, 2011). This syntenic mutation combination has been detected alone, in trans with various other POLG mutations and alterations, and as homozygous, in individuals with Alpers syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability, and various other POLG-deficiency symptoms (Van Goethem, 2003; Uusimaa, 2013; Weiss, 2010; Horvath, 2006; Tang, 2011). Of note, this mutation has been detected without p.T251I in conjunction with the p.R853W alteration (phase was not confirmed) in an individual with PEO, ptosis, and multiple mtDNA deletions (González-Vioque, 2006). Biochemical characterization of P587L mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than P587L alone (DeBalsi, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jan 04, 2021

- -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 22, 2021

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Medico-Diagnostic Laboratory Genica

Oct 19, 2022

The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was found with an allele frequency of 0.1540% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. In silico analysis by Polyphen-2, SIFT and Mutation-Taster predicted it as damaging. The amino acid change is in a highly conserved position and proline and leucine have moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.752C>T in a patient with Hypertrophic cardiomyopathy. The patient is also carrier of variants GTPBP3(NM_032620.4):c.181G>C and GTPBP3(NM_032620.4):c.1199C>T in compound heterozygous state. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 24, 2019

- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 15, 2014

- -

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Tip-toe gait Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Feb 10, 2021

c.1760C>T p.(Pro587Leu) [dbSNP: rs113994096, Frequenz: A=0.15%, GnomAD] is rated by the majority (15 entries) as "probably pathogenic" and "pathogenic" in the ClinVar mutation database. -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Stroke disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PM1,PM2,PP3,BP1 -

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant classified as Pathogenic and reported on 04-20-2016 by Children's National Medical Center. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.091	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.66
MVP		0.97
MPC		0.66
ClinPred		0.071	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.79
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994096; hg19: chr15-89868870; COSMIC: COSV105090786; COSMIC: COSV105090786;