Submissions for variant NM_001005361.3(DNM2):c.8A>G (p.Asn3Ser)

gnomAD frequency: 0.00003  dbSNP: rs890297188

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004732477	SCV005367872	benign	Centronuclear myopathy	2024-08-07	reviewed by expert panel	curation	The c.8A>G variant in DNM2 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 3. The highest population filtering allele frequency in gnomAD v4.1 is 0.00001190 (2/43076 alleles) in the Admixed American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.57, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/24)
GeneDx	RCV000479544	SCV000574206	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791747	SCV000931008	uncertain significance	Charcot-Marie-Tooth disease dominant intermediate B	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 3 of the DNM2 protein (p.Asn3Ser). 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 variant has not been reported in the literature in individuals affected with DNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 424401). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DNM2 protein function with a positive 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000479544	SCV001712952	uncertain significance	not provided	2020-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002526985	SCV003612706	uncertain significance	Inborn genetic diseases	2024-10-09	criteria provided, single submitter	clinical testing	The c.8A>G (p.N3S) alteration is located in exon 1 (coding exon 1) of the DNM2 gene. This alteration results from a A to G substitution at nucleotide position 8, causing the asparagine (N) at amino acid position 3 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000479544	SCV003830499	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing