Submissions for variant NM_001927.4(DES):c.1353C>G (p.Ile451Met) (rs121913002)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056787	SCV000235800	uncertain significance	not provided	2018-10-04	criteria provided, single submitter	clinical testing	The I451M variant in the DES gene has been reported in association with both DCM and skeletal myopathy (Li et al., 1999; Dalakas et al., 2000; Dalakas et al., 2003; Miyamoto et al., 2001). Li et al., (1999) identified I451M in a proband with familial DCM and not in 460 healthy control individuals, and reported that I451M co-segregated with disease in all affected family members; however, the variant exhibited incomplete penetrance. Miyamoto et al. (2000) identified I451M in 3/265 (1.1%) of Japanese patients with DCM and did not observe I451M in 359 healthy controls. Additionally, Dalakas et al. (2000; 2003) identified I451M in three individuals from a family affected with skeletal myopathy, without features of cardiomyopathy. The I451M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I451M variant is located in the tail domain of the human desmin protein (Li et al., 1999). Nevertheless, the I451M variant is a conservative amino acid substitution as these residues share similar properties, and is least likely to impact secondary structure. Although functional studies have shown that I451M mutants exhibit apparently normal intermediate filament network formation, I451M appears to interfere with binding to desmoplakin in vitro and disrupts localization to the Z-disc in transgenic mice (Lapouge et al., 2006; Mavroidis et al., 2008). Missense variants in nearby residues (K449M, K449T, T453I, R454W) have been reported in association with cardiomyopathy and desmin related myopathy, further supporting the functional importance of this region of the protein. In summary, I451M in the DES gene is interpreted as a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000056787	SCV000343109	uncertain significance	not provided	2016-08-12	criteria provided, single submitter	clinical testing
Invitae	RCV000698481	SCV000827147	uncertain significance	Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R	2019-03-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 451 of the DES protein (p.Ile451Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs121913002, ExAC 0.02%). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 11728149) and has been described to segregate with evidence of incomplete penetrance in a family with dilated cardiomyopathy (PMID: 10430757) and in a family with myofibrillar myopathy (PMID: 10717012). ClinVar contains an entry for this variant (Variation ID: 16824). Experimental studies have shown that this missense change is not expected to disrupt desmin protein assembly, but interferes with intermediate filament interactions in vitro (PMID: 17105773, 17221859) and inhibits desmin stabilization and its localization to the Z disc in transgenic mice (PMID: 18539904). 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.
Illumina Clinical Services Laboratory,Illumina	RCV001140631	SCV001300905	uncertain significance	Myofibrillar myopathy 1	2018-07-10	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000018318	SCV001300906	uncertain significance	Dilated cardiomyopathy 1I	2017-11-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001140632	SCV001300907	benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
OMIM	RCV000018318	SCV000038597	pathogenic	Dilated cardiomyopathy 1I	1999-08-03	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056787	SCV000087900	not provided	not provided		no assertion provided	not provided