ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1371+1G>A

gnomAD frequency: 0.00005  dbSNP: rs748323823
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183362 SCV000235802 uncertain significance not provided 2023-08-03 criteria provided, single submitter clinical testing Canonical splice site variant with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918)
Invitae RCV000458158 SCV000552180 uncertain significance Desmin-related myofibrillar myopathy 2022-10-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the DES gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs748323823, gnomAD 0.07%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal dominant dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 201714). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV000622142 SCV000736012 uncertain significance Cardiovascular phenotype 2019-01-22 criteria provided, single submitter clinical testing The c.1371+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the DES gene. This alteration disrupts the highly conserved canonical splice donor site and is expected to cause aberrant splicing. Internal RNA studies indicate that this alteration leads to the utilization of a cryptic donor site seven nucleotides downstream of the canonical splice donor site, causing a translational frameshift with a predicted alternate stop codon (p.V459Sfs*5) (Ambry internal data). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of DES, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 12 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
AiLife Diagnostics, AiLife Diagnostics RCV000183362 SCV002501867 likely pathogenic not provided 2022-03-09 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223904 SCV000280068 uncertain significance not specified 2013-01-18 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

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