Submissions for variant NM_002180.3(IGHMBP2):c.1693G>A (p.Asp565Asn)

gnomAD frequency: 0.00002  dbSNP: rs770111639

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705582	SCV000834584	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 565 of the IGHMBP2 protein (p.Asp565Asn). This variant is present in population databases (rs770111639, gnomAD 0.01%). This missense change has been observed in individual(s) with distal hereditary motor neuropathy, type VI (PMID: 14681881, 15108294, 22157136). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 581680). 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 expected to disrupt IGHMBP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IGHMBP2 function (PMID: 19158098, 22157136). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090413	SCV001245955	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	IGHMBP2: PM3:Very Strong, PM2, PP3, PS3:Supporting
Ambry Genetics	RCV002397478	SCV002712391	likely pathogenic	Inborn genetic diseases	2021-05-12	criteria provided, single submitter	clinical testing	The c.1693G>A (p.D565N) alteration is located in exon 12 (coding exon 12) of the IGHMBP2 gene. This alteration results from a G to A substitution at nucleotide position 1693, causing the aspartic acid (D) at amino acid position 565 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the IGHMBP2 c.1693G>A alteration was observed in 0.002% (7/282810) of total alleles studied, with a frequency of 0.01% (1/10370) in the Ashkenazi Jewish subpopulation. This alteration has been reported in trans with a pathogenic alteration in an individual with spinal muscular atrophy 1 with respiratory distress (SMARD1) (Maystadt, 2004). It was also reported in trans with a different alteration in a child with developmental delay, motor deterioration, myotonia, reduced tendon reflexes, slurred speech, abnormal posturing, poor fine motor coordination, peripheral neuropathy, talipes equinovarus, and EMG abnormality (Gao, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration has also been shown to impair protein function (Eckart, 2012; Guenther, 2009). The in silico prediction for the p.D565N alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000768429	SCV005184364	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2S	2024-05-01	criteria provided, single submitter	clinical testing	Variant summary: IGHMBP2 c.1693G>A (p.Asp565Asn) results in a conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal domain (IPR041679) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251404 control chromosomes. c.1693G>A has been reported in the literature in at-least two individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and Spinal Muscular Atrophy with Respiratory Distress (examples, Maystadt_2004, Xiao_2022, Gao_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely inactive in the helicase assay, but still retained its full nucleic acid binding capacity in FM3A cells (Guenther_2009). The following publications have been ascertained in the context of this evaluation (PMID: 34986626, 31178897, 19158098, 15108294). ClinVar contains an entry for this variant (Variation ID: 581680). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000705582	SCV005630263	likely pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-05-07	criteria provided, single submitter	clinical testing
Biochemistry Laboratory of CDMU, Chengde Medical University	RCV000768429	SCV000899184	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2S		no assertion criteria provided	case-control
Inherited Neuropathy Consortium	RCV000790283	SCV000929687	uncertain significance	Distal spinal muscular atrophy		no assertion criteria provided	literature only