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

dbSNP: rs121913002

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056787	SCV000235800	uncertain significance	not provided	2025-02-03	criteria provided, single submitter	clinical testing	Reported previously in three affected relatives from one family with skeletal myopathy; however, only the DES gene was analyzed in these individuals (PMID: 12609507); Reported previously in association with DCM and HCM, and was shown to segregate with disease in one affected relative from a single family; however, only the DES gene was analyzed in this family (PMID: 10430757, 30847666, 37466024); Functional studies have been inconsistent in demonstrating a damaging effect (PMID: 17105773, 18539904, 28470624, 12609507, 17221859, 21262226); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36935760, 16761416, 11052860, 21262226, 17221859, 28470624, 18539904, 16979163, 30403391, 26807690, 30847666, 37466024, 17105773, 10430757, 10717012, 11310634, 11728149, 12609507)
Eurofins Ntd Llc (ga)	RCV000056787	SCV000343109	uncertain significance	not provided	2016-08-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698481	SCV000827147	uncertain significance	Desmin-related myofibrillar myopathy	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 451 of the DES protein (p.Ile451Met). This variant is present in population databases (rs121913002, gnomAD 0.02%). This missense change has been observed in individual(s) with DES-related conditions (PMID: 10430757, 10717012, 11728149, 30403391, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16824). 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) has been performed 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 DES protein function. Experimental studies have shown that this missense change affects DES function (PMID: 17105773, 17221859, 18539904, 28470624). 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 Laboratory Services, Illumina	RCV000698481	SCV001300905	uncertain significance	Desmin-related myofibrillar myopathy	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 Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265561	SCV002548221	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: DES c.1353C>G (p.Ile451Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233386 control chromosomes. The observed variant frequency is approximately 2.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.1353C>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (DCM) (example, Li_1999, Miyamoto_2001, van Lint_2019), in unaffected family members (example, Li_1999, Dalakas_2003), and individuals with skeletal myopathy without DCM (example, Dalakas_2000, Dalakas_2003). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Dalakas_2003, Mavrodis_2008). One study reported that this variant was functional and normally interacted with other intermediate filaments (Dalakas_2003) while another reported that mutant desmin loses its Z-disc localization but it can still associate with the intercalated discs, which, however, have an altered architecture, resembling other examples of dilated cardiomyopathy (Mavrodis_2008). These results however, do not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004018640	SCV004856351	uncertain significance	Cardiovascular phenotype	2020-12-30	criteria provided, single submitter	clinical testing	The c.1353C>G (p.I451M) alteration is located in exon 8 (coding exon 8) of the DES gene. This alteration results from a C to G substitution at nucleotide position 1353, causing the isoleucine (I) at amino acid position 451 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV004018640	SCV006066783	likely pathogenic	Cardiovascular phenotype	2022-07-12	criteria provided, single submitter	clinical testing
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
Clinical Genetics, Academic Medical Center	RCV000056787	SCV001925897	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000056787	SCV001963222	likely pathogenic	not provided		no assertion criteria provided	clinical testing