ClinVar Miner

Submissions for variant NM_004415.3(DSP):c.2131_2132delAG (p.Ser711Cysfs) (rs587782927)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000143886 SCV000188755 likely pathogenic Primary dilated cardiomyopathy 2013-12-04 no assertion criteria provided clinical testing
GeneDx RCV000256098 SCV000321564 pathogenic not provided 2016-05-26 criteria provided, single submitter clinical testing This variant causes a shift in reading frame starting at codon Serine 711, changing it to a Cysteine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Ser711CysfsX4. Pigors M et al. (2015) described this variant in a single family: a 14-year-old male, who also inherited a missense DSP variant, with a diagnosis of dilated cardiomyopathy (DCM) with severe left ventricle insufficiency leading to a cardiac transplant, and a 10-year-old sister, who only inherited c.2131_2132delAG, who also had a diagnosis of DCM, plantar keratosis and hypotrichosis. The variant was maternally inherited; the mother had very curly hair and a diagnosis of mild bradycardia (Pigors et al., 2015). This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Approximately 50% of published variants in the DSP gene are predicted to lead to premature termination of protein translation. Other frameshift variants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014). Lastly, the c.2131_2132delAG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.2131_2132delAG in the DSP gene is interpreted as a disease-causing variant.
Strand Center for Genomics and Personalized Medicine,Strand Life Sciences Pvt Ltd RCV000133469 SCV000188540 likely pathogenic Left ventricular noncompaction cardiomyopathy; Ventricular tachycardia no assertion criteria provided clinical testing This variant was found heterozygously in 2 sisters (age, mid twenties, early thirties), both suffering from Ventricular Tachycardia and Left Ventricular disease, possibly Left Ventricular Non-Compaction. One sister shows severe Heart Failure. Yet another sister in her early thirties in this family passed away due to Sudden Cardiac Arrest; this sister was not sequenced. Their father is reported to have passed away in his forties of cardiac failure. Whole exome sequencing on these two sisters followed by interpretation of about 200 genes reported to cause cardiac malfunction yielded this variant as the prime candidate. The only other potentially interesting variants found were missense VUS''s in the TTN and LAMA4. This variant causes premature truncation of DSP after 713 amino acids instead of the usual 2871 amino acids. DSP connects desmin filaments to desmosomes, the rivets that hold neighboring cardiac muscle cells together. Truncating variants in one copy of DSP have been reported in a number of individuals with ARVD and DCM (PMID: 21606390,24503780). However, there are also several reports of one copy truncations without any clinical symptoms (PMID: 23137101). So truncations are possibly of limited penetrance. For all variants over all desmosomal genes, this penetrance is estimated to be 35% by age 40 and 60% lifelong. Heterozygous knockout mice models do show early death and heart disease (PMID: 16823493,22240500). DSP variants are typically associated with right ventricular disease, but left ventricular involvement with disease progress is common. There are also purely left ventricular instances reported (PMID: 16061754), due to a truncation at aa 586, which is close to the truncation in this case.

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