Submissions for variant NM_001303256.3(MORC2):c.2644G>A (p.Ala882Thr)

gnomAD frequency: 0.00005  dbSNP: rs372199572

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815989	SCV000956473	uncertain significance	Charcot-Marie-Tooth disease axonal type 2Z	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 882 of the MORC2 protein (p.Ala882Thr). This variant is present in population databases (rs372199572, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MORC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 659050). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MORC2 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056596	SCV005726321	likely benign	not specified	2024-11-14	criteria provided, single submitter	clinical testing	Variant summary: MORC2 c.2644G>A (p.Ala882Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251388 control chromosomes. The observed variant frequency is approximately 70 fold of the estimated maximal expected allele frequency for a pathogenic variant in MORC2 causing Charcot-Marie-Tooth disease axonal type 2Z phenotype (6.3e-07). To our knowledge, no occurrence of c.2644G>A in individuals affected with Charcot-Marie-Tooth disease axonal type 2Z and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 659050). Based on the evidence outlined above, the variant was classified as likely benign.