Submissions for variant NM_203290.4(POLR1C):c.193A>G (p.Met65Val)

gnomAD frequency: 0.00100  dbSNP: rs141471029

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000390190	SCV000463446	uncertain significance	POLR1C-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.193A>G (p.Met65Val) variant has been reported in one study in which it is found in a compound heterozygous state with another missense variant in an individual with a clinical phenotype of leukodystrophy, hypomyelinating (Thiffault et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Met65Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for POLR1C-related disorders.
Illumina Laboratory Services, Illumina	RCV000778794	SCV000915165	uncertain significance	Hypomyelinating leukodystrophy 11	2017-09-05	criteria provided, single submitter	clinical testing	The POLR1C c.193A>G (p.Met65Val) missense variant has been reported in one study in which it is found in a compound heterozygous state with another missense variant in an individual with hypomyelinating leukodystrophy (Thiffault et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Met65Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Pol III-related leukodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
MyeliNeuroGene Lab, McGill University Health Center Research Institute	RCV000778794	SCV000924590	pathogenic	Hypomyelinating leukodystrophy 11		criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000778794	SCV001440015	uncertain significance	Hypomyelinating leukodystrophy 11	2019-01-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375152	SCV001572110	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PP3_Supporting, BS1_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001814980	SCV002051432	uncertain significance	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: POLR1C c.193A>G (p.Met65Val) results in a conservative amino acid change located in the DNA-directed RNA polymerase, RpoA/D/Rpb3-type (IPR011263) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 1614026 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in POLR1C causing POLR1C-Related Disorders, however published literature suggests biallelic individuals are expected to have early onset severe disease incompatible with homozygous controls. c.193A>G has been reported in the literature in the presumed or confirmed compound heterozygous state at least 4 individuals affected with clinical features of Hypomyelinating Leukodystrophy (example, Thiffault_2015, Gauquelin_2019, Ching-Lopez_2021, Schluter_2022), including at least 1 individual who carried a pathogenic variant in trans. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33804237, 32042905, 35012964, 26151409). ClinVar contains an entry for this variant (Variation ID: 356872). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001814980	SCV002062020	uncertain significance	not specified	2017-11-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861282	SCV002196685	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the POLR1C protein (p.Met65Val). This variant is present in population databases (rs141471029, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with POLR1C-related conditions (PMID: 26151409, 32042905, 33804237). ClinVar contains an entry for this variant (Variation ID: 356872). 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 POLR1C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001861282	SCV002586118	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022026	SCV005008705	uncertain significance	Inborn genetic diseases	2021-05-21	criteria provided, single submitter	clinical testing	The c.193A>G (p.M65V) alteration is located in exon 3 (coding exon 3) of the POLR1C gene. This alteration results from a A to G substitution at nucleotide position 193, causing the methionine (M) at amino acid position 65 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001861282	SCV005078229	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26151409, 34426522, 33804237, 32042905)
GeneReviews	RCV000778794	SCV001760708	not provided	Hypomyelinating leukodystrophy 11		no assertion provided	literature only