rs113994094

chr15-89330184-G-Achr15-89330184-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_002693.3(POLG):c.752C>T(p.Thr251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,784 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T251P) has been classified as Uncertain significance.

• 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:38 U:7 O:3
• Conservation: PhyloP100: 2.59

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 15-89330184-G-A is Pathogenic according to our data. Variant chr15-89330184-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13503.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=3, Uncertain_significance=7, Pathogenic=25, Likely_pathogenic=9}. Variant chr15-89330184-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-89330184-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13515529).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.752C>T	p.Thr251Ile	missense_variant	3/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*24C>T		3_prime_UTR_variant	3/23
POLG	NM_001126131.2	c.752C>T	p.Thr251Ile	missense_variant	3/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.752C>T	p.Thr251Ile	missense_variant	3/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1			downstream_gene_variant				P1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

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: 389 AN: 251268 Hom.: 1 AF XY: 0.00161 AC XY: 219 AN XY: 135894

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00203 AC: 2965 AN: 1461440 Hom.: 2 Cov.: 32 AF XY: 0.00197 AC XY: 1429 AN XY: 727040

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000546

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74492

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00246 Hom.: 1

Bravo AF: 0.00158

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00170 AC: 207

EpiCase AF: 0.00262

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:38 Uncertain:7 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:10 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -
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	Dec 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 28, 2022	- -
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	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2023	PM3_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	The T251I missense variant in the POLG gene has been reported previously in association with several POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). The T251I missense variant is typically found on the same allele (in cis) with the P587L variant and together they account for approximately 6% of disease-causing alleles in the POLG gene (Tang et al., 2011); however, the P587L variant was not observed in this patient. The T251I variant is observed in 195/66,122 (0.3%) alleles from individuals of European background, including 1 unrelated homozygous individual in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T251I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution alters at a poorly conserved residue predicted to be in the exonuclease domain. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret T251I as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2019	Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Progressive sclerosing poliodystrophy Pathogenic:6 Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	May 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Uncertain significance, 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.752C>T (NP_002684.1:p.Thr251Ile) [GRCH38: NC_000015.10:g.89330184G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Dec 12, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 251 of the POLG protein (p.Thr251Ile). This variant is present in population databases (rs113994094, 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 variant, p.Pro587Leu (PMID: 12210792, 15349879, 18546365, 19251978, 19566497, 19578034, 30423451, 30936349, 33396418). 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. Additionally, the p.Thr251Ile variant has been observed independent from the p.Pro587Leu variant in individual(s) with autosomal recessive POLG-related conditions (PMID: 12707443, 22616202, 23921535). ClinVar contains an entry for this variant (Variation ID: 13503). 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 not expected to disrupt POLG protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 22, 2020	This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (gnomAD 434/282672 heterozygotes, 1 homozygote). The variant has been reported in dbSNP (rs113994094). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13503). The two POLG variants (c.1760C>T and c.752C>T) detected in this patient have been reported in many individuals affected with POLG-related diseases, and in almost all cases they have been observed on the same chromosome (in cis) (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). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
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. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013503). The variant was observed in cis with NM_002693.3:c.1760C>T (p.Pro587Leu) 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	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2022	- -

POLG-related disorder Pathogenic:3 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 01-29-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 02, 2022	PS3, PM3_Very Strong, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.752C>T;p.(Thr251Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 13503; OMIM 174763.0007; PMID: 12210792; 12825077; 15349879; 26224072; 26742794PS4. The p.(Thr251Ile) was detected in trans with a pathogenic variant (PMID: 20385918) - PM3. 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:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 27, 2021	This variant was identified as compound heterozygous with NM_001126131.2:c.1760C>T. -
Uncertain significance, 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 3 of the POLG gene that results in the amino acid substitution of Isoleucine for Threonine at codon251 was detected. The observed variant c.752C>T (p.Thr251lle) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases respectively. The in silico prediction of the variant is benign 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 a variant of uncertain significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
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 -

POLG-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.752C>T (p.T251I) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 752, causing the threonine (T) at amino acid position 251 to be replaced by an isoleucine (I). Based on the available evidence, the c.752C>T (p.T251I) 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.752C>T alteration was observed in 0.15% (434/282672) of total alleles studied, with a frequency of 0.27% (344/129038) in the European (non-Finnish) subpopulation. This mutation has been reported to occur almost exclusively in cis with p.P587L (c.1760C>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, possible Kearns-Sayre syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability, and various other POLG-deficiency symptoms (Dames, 2013; Van Goethem, 2003; Blok, 2009; Uusimaa, 2013; Weiss, 2010; Horvath, 2006; Tang, 2011). Of note, this mutation has been detected without p.P587L (c.1760C>T) in an individual with Parkinson disease without another POLG alteration and in another individual who also carried POLG p.G848S (phase was not confirmed) with sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO) (Gáti, 2011; Gui, 2015). Biochemical characterization of T251I 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 T251I alone (DeBalsi, 2017). This alteration is predicted to be tolerated 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 0.1535% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. The variant has conflicting predictions of pathogenicity, based on in silico data analysis (Polyphen-2 and SIFT - benign, Mutation-Taster - disease causing), with the position being poorly conserved and threonine and isoleucine having moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.1760C>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

- -

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

The variant c.752C> T p. (Thr251Ile) [dbSNP: rs113994094, frequency: 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

- -

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

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/. -

Mitochondrial disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	0.80	N;N
MutationTaster	Benign	9.9e-11	A;A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.21	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0010	B;B
Vest4		0.34
MVP		0.86
MPC		0.16
ClinPred		0.010	T
GERP RS		3.6
Varity_R		0.031
gMVP		0.34

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: rs113994094; hg19: chr15-89873415; COSMIC: COSV105090787; COSMIC: COSV105090787;