Submissions for variant NM_002693.3(POLG):c.35C>T (p.Ala12Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003194759	SCV003898542	uncertain significance	Inborn genetic diseases	2023-02-13	criteria provided, single submitter	clinical testing	The c.35C>T (p.A12V) alteration is located in exon 2 (coding exon 1) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 35, causing the alanine (A) at amino acid position 12 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003779701	SCV004631257	uncertain significance	Progressive sclerosing poliodystrophy	2023-07-07	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 2483175). This variant has not been reported in the literature in individuals affected with POLG-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the POLG protein (p.Ala12Val).