Submissions for variant NM_002693.3(POLG):c.3317T>C (p.Val1106Ala)

gnomAD frequency: 0.00001  dbSNP: rs1354582663

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623937	SCV000743020	likely pathogenic	Inborn genetic diseases	2017-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003626635	SCV004534648	likely pathogenic	Progressive sclerosing poliodystrophy	2023-07-03	criteria provided, single submitter	clinical testing	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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val1106 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 15349879), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects POLG function (PMID: 26077851). ClinVar contains an entry for this variant (Variation ID: 522129). This missense change has been observed in individual(s) with POLG-related conditions (PMID: 26077851, 33469851). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.1%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1106 of the POLG protein (p.Val1106Ala).
Neuberg Centre For Genomic Medicine, NCGM	RCV004546534	SCV005042919	likely pathogenic	Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing	The missense c.3317T>C p.Val1106Ala variant in the POLG gene has been reported previously in compound heterozygous state in patients affected with mitochondrial disease. Functional studies done in yeast model shows the variant effects mRNA stability Deepha S, et al., 2021; Kaliszewska M, et al., 2015. Evidence on the variant being pathogenic in homozygous state is not available. This variant is located in a mutational hot spot. A different missesne variant p.Val1106Ile has been reported in patients with POLG-related mitochondrial disease Stumpf JD, et al., 2013. The variant has allele frequency 0.003% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/Uncertain Significace. The amino acid Val at position 1106 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val1106Ala in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Additional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689813	SCV005185503	likely pathogenic	Mitochondrial DNA depletion syndrome	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3317T>C (p.Val1106Ala) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-06 in 1614112 control chromosomes. c.3317T>C has been reported in the literature in compound heterozyous or homozygous individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (Deepha_2021, Kaliszewska_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a reduction in mitochondrial genome stability in a yeast model (Kaliszewska_2015). The following publications have been ascertained in the context of this evaluation (PMID: 33469851, 26077851). ClinVar contains an entry for this variant (Variation ID: 522129). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005004274	SCV005633368	likely pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2024-05-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765236	SCV000896472	uncertain significance	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2018-10-31	flagged submission	clinical testing