Submissions for variant NM_001927.4(DES):c.407T>A (p.Leu136His)

gnomAD frequency: 0.00011  dbSNP: rs397516695

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037241	SCV000060898	uncertain significance	not specified	2013-07-18	criteria provided, single submitter	clinical testing	The Leu136His variant in DES has been identified by our laboratory in 1 individu al with DCM (LMM unpublished data). Data from large population studies is insuff icient to assess the frequency of this variant. Leucine (Leu) at position 136 is conserved in mammals, but not in more evolutionarily distant species. However, other computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. Additional infor mation is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000726980	SCV000235812	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy, primary electrical disease, and neuromuscular disease (Pugh et al., 2014; Wilson et al., 2015; Proost et al., 2017; Campuzano et al., 2020; Gonzalez-Quereda L et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32268277, 28341588, 30564623, 24503780, 32403337, 33823640, 30755392, 26265630, 36497166, 26807690)
Invitae	RCV000528546	SCV000654174	uncertain significance	Desmin-related myofibrillar myopathy	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the DES protein (p.Leu136His). This variant is present in population databases (rs397516695, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 26265630, 28341588, 30755392, 32403337). ClinVar contains an entry for this variant (Variation ID: 44261). 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 DES protein function with a positive predictive value of 95%. 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.
Eurofins Ntd Llc (ga)	RCV000726980	SCV000704645	uncertain significance	not provided	2017-08-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618538	SCV000736262	uncertain significance	Cardiovascular phenotype	2022-11-18	criteria provided, single submitter	clinical testing	The p.L136H variant (also known as c.407T>A), located in coding exon 1 of the DES gene, results from a T to A substitution at nucleotide position 407. The leucine at codon 136 is replaced by histidine, an amino acid with similar properties. This variant was reported in 2 individuals with dilated cardiomyopathy (DCM) and in an individual reported to have arrhythmogenic cardiomyopathy (Pugh TJ et al., Genet. Med. 2014 Aug; 16(8):601-8; Wilson KD et al., Circ. Res. 2015 Sep; 117(7):603-11; Campuzano O et al. EBioMedicine. 2020 Apr;54:102732). This variant has also been detected in cohorts with varying phenotypes including a pediatric exome sequencing cohort and probands with sudden death, long QT syndrome, and unspecified neuromuscular disorder; however, clinical details were limited (Proost D et al. J Mol Diagn. 2017 05;19(3):445-459; Ji J et al. Cold Spring Harb Mol Case Stud. 2019 04;5(2); Gonzalez-Quereda L et al. Genes (Basel). 2020 05;11(5)). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735343	SCV000854497	uncertain significance	Myopathy; Respiratory distress; Proximal muscle weakness; Pulmonary alveolar proteinosis; Generalized hypotonia; Neonatal hypotonia; Restrictive ventilatory defect; Neonatal respiratory distress; Respiratory insufficiency due to muscle weakness; Skeletal myopathy; Abnormal pulmonary interstitial morphology; Congenital peripheral neuropathy; Proximal muscle weakness in upper limbs; Infantile axial hypotonia		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798112	SCV002043133	uncertain significance	Cardiomyopathy	2020-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504889	SCV002814446	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2022-04-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726980	SCV003829039	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037241	SCV003922856	uncertain significance	not specified	2023-03-08	criteria provided, single submitter	clinical testing	Variant summary: DES c.407T>A (p.Leu136His) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 181860 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.407T>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Primary electrical disease (Pugh_2014, Wilson_2015, Proost_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000037241	SCV000280071	uncertain significance	not specified	2014-12-07	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we consider this variant a variant of uncertain significance. This is a novel variant. This is a non-conservative amino acid change of a hydrophobic leucine to a hydrophilic histidine. The leucine at codon 136 is well conserved across evolution (except in chickens). PolyPhen2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The leucine at codon 136 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,700 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 136 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/30/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/30/13).