Submissions for variant NM_003321.5(TUFM):c.622G>A (p.Glu208Lys)

gnomAD frequency: 0.00062  dbSNP: rs143189885

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197002	SCV000252434	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Illumina Laboratory Services, Illumina	RCV000327030	SCV000396363	uncertain significance	Combined oxidative phosphorylation defect type 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197002	SCV003252446	uncertain significance	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 208 of the TUFM protein (p.Glu208Lys). This variant is present in population databases (rs143189885, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with TUFM-related conditions. ClinVar contains an entry for this variant (Variation ID: 215311). 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 TUFM 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.
Ambry Genetics	RCV002515444	SCV003563562	uncertain significance	Inborn genetic diseases	2021-07-19	criteria provided, single submitter	clinical testing	The c.622G>A (p.E208K) alteration is located in exon 5 (coding exon 5) of the TUFM gene. This alteration results from a G to A substitution at nucleotide position 622, causing the glutamic acid (E) at amino acid position 208 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000197002	SCV003917505	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000197002	SCV005411277	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	BP4, PM2_moderate