ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8330C>A (p.Pro2777His)

gnomAD frequency: 0.00001  dbSNP: rs376273136
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181349 SCV000233648 uncertain significance not provided 2021-09-17 criteria provided, single submitter clinical testing Reported in a 3-year-old male who underwent clinical exome sequencing due to LQTS that presented with cardiac arrest; he was found to harbor a de novo CALM1 variant, whereas the P2777H variant in the DSP gene was inherited from his asymptomatic mother (normal QTc) (Pipilas et al., 2016); Reported in an individual with left ventricular hypertrabeculation who harbored an additional missense variant in the GATA4 gene (Miszalski-Jamka et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199909; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 28784889, 28798025, 27374306)
Color Diagnostics, LLC DBA Color Health RCV001178812 SCV001343346 uncertain significance Cardiomyopathy 2023-03-31 criteria provided, single submitter clinical testing This missense variant replaces proline with histidine at codon 2777 of the DSP protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a child affected with long QT syndrome as well as in an unaffected parent (PMID: 27374306, 28784889). It has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001219435 SCV001391373 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2022-10-26 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2777 of the DSP protein (p.Pro2777His). This variant is present in population databases (rs376273136, gnomAD 0.0009%). This missense change has been observed in individual(s) with left ventricular hypertrabeculation (PMID: 28798025). ClinVar contains an entry for this variant (Variation ID: 199909). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 RCV002433789 SCV002677152 uncertain significance Cardiovascular phenotype 2023-01-31 criteria provided, single submitter clinical testing The p.P2777H variant (also known as c.8330C>A), located in coding exon 24 of the DSP gene, results from a C to A substitution at nucleotide position 8330. The proline at codon 2777 is replaced by histidine, an amino acid with similar properties. This variant was detected in a child with long QT syndrome who also had a reportedly de novo CALM1 variant and a GJA5 variant detected; his unaffected mother carried both the DSP and GJA5 variants (Pipilas DC et al. Heart Rhythm, 2016 10;13:2012-9). This variant was also reported in an individual with left ventricular hypertrabeculation (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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