ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2071C>T (p.Leu691Phe) (rs1363445022)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641817 SCV000763467 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-08-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 691 of the DSP protein (p.Leu691Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786306 SCV000925071 uncertain significance not provided 2017-10-25 no assertion criteria provided provider interpretation Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results included 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Leu691Phe (c.2071C>T) in exon 15 of the DSP gene (NM_004415.2) Chromosome location 6:7572242 C / T Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. Of note, most Likely Pathogenic and Pathogenic variants in DSP listed in ClinVar are not missense but are instead truncating loss-of-function variants (nonsense, frameshift, or splice-site variants). The DSP gene is associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 336069) and dilated cardiomyopathy (DCM) with woolly hair, keratoderma and tooth agenesis (MedGen UID: 808093), as well as autosomal recessive DCM with woolly hair and keratoderma (MedGen UID: 340124). Additional DSP-related conditions have been reported (OMIM: 125647). These conditions do not match Joshua's clinical presentation. This is a conservative amino acid change, resulting in the replacement of a nonpolar Leucine with a nonpolar Phenylalanine. Leucine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is frequently replaced by another amino acid, including a nonpolar Isoleucine, Methionine, Valine, Alanine, Proline, or with a polar Cysteine or Threonine. Kapplinger et al. have proposed a “hot spot” for DSP missense variants between amino acids 250-604 in patients with ARVC but not in controls. This variant does not fall within that hot spot. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of missense change. According to the Invitae report, 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 2 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 1 Finnish European and 1 non-Finnish European individual (for the highest allele frequency, with large error bars: 0.004%), overall MAF 0.0008%. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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