Submissions for variant NM_006393.3(NEBL):c.658G>A (p.Val220Met)

dbSNP: rs571563897

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208415	SCV000264122	uncertain significance	Primary dilated cardiomyopathy	2015-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000494255	SCV000581892	uncertain significance	not provided	2017-05-03	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NEBL gene. The V220M variant has notbeen published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory in association with DCM(ClinVar SCV000264122.1; Landrum et al., 2016). The V220M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and methionine (M) is the wild-type residue at this position in at least two mammalian species.Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. Nevertheless, the V220M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000208415	SCV002145527	uncertain significance	Primary dilated cardiomyopathy	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 220 of the NEBL protein (p.Val220Met). This variant is present in population databases (rs571563897, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 222750). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV004020560	SCV004980160	uncertain significance	not specified	2023-09-20	criteria provided, single submitter	clinical testing	The c.658G>A (p.V220M) alteration is located in exon 7 (coding exon 7) of the NEBL gene. This alteration results from a G to A substitution at nucleotide position 658, causing the valine (V) at amino acid position 220 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.