ClinVar Miner

Submissions for variant NM_172244.3(SGCD):c.717C>G (p.Asp239Glu) (rs180898690)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172106 SCV000055145 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041411 SCV000065106 benign not specified 2014-11-06 criteria provided, single submitter clinical testing p.Asp239Glu in exon 8 of SGCD: This variant is not expected to have clinical sig nificance because has been reported in multiple Asian individuals with various c ardiomyopathies and did not segregate with disease in 2 affected relatives in on e family. In addition, it has been identified in 0.3% (2/572) of Asian chromosom es by the 1000 Genomes Project (dbSNP rs180898690) and in 1.5% (54/3652) East As ian chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinst
GeneDx RCV000041411 SCV000236386 likely benign not specified 2017-08-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000670909 SCV000795823 likely benign Dilated cardiomyopathy 1L; Autosomal recessive limb-girdle muscular dystrophy type 2F 2017-11-19 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172106 SCV000843830 benign not provided 2017-09-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000041411 SCV000857771 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000041411 SCV000280486 uncertain significance not specified 2014-06-02 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. IVS12+1 G>A (c.2489+1 G>A) in the PKP2 gene This is a variant that we can have high confidence causes ARVC. It has been reported previously in multiple patients with ARVC, from multiple ethnicities, and also in multiple unrelated individuals tested for ARVC at the testing laboratory, according to their report. It is a splice-site variant that destroys the canonical splice donor site in intron 12. It is expected to cause abnormal gene splicing, which may lead to protein truncation or absence of protein due to mRNA decay. At least 24 patients with this specific variant have been published in the literature. Gerull et al. (2004) identified it in 1 ARVC proband of Western European descent. Dalal et al. (2006) found it in 3 unrelated patients with ARVC from the Johns Hopkins registry– and den Haan et al. (2009) added 1 more North American patient to this group. Age at first symptom for these patients ranged from 22-51 years. [Reports by Dalal et al. (2009) and Tan et al. (2010) appear to refer to these same patients.] van Tintelen et al. (2006) found the variant in 3 unrelated Dutch Caucasian individuals with ARVC. Of the cohort studied, patients with this variant had the youngest age of onset (ages 17, 17, and 20). Haplotype analysis indicated that it may be a founder mutation. One patient also carried a missense variant in PKP2: p.Glu62Lys. [Bhuiyan et al. (2009) appears to refer to the same patients as the van Tintelen et al. study.] Cox et al. 2011 identified it in 6 index patients (it is unclear how many of these were in the prior paper by van Tintelen et al. 2006 from the same group); two patients also carried a missense variant in DSG2 or JUP. Two 16-year-old males in one of these families suffered sudden cardiac death. Wlodarska et al. 2008 saw it in at least one Polish patient. Fressart et al. (2010) found it in 3 unrelated individuals recruited in France and/or Switzerland. Quarta et al. (2011) saw it in one patient referred to a center in London. Palmisano et al. (2011) studied a young male athlete with aborted cardiac arrest at age 21 and his affected but asymptomatic father, who both carried this variant and also a DSC2 I109M variant. The family’s ancestry may have been from Iran. Nakajima et al. (2012) found the variant in a Japanese patient who also carried the PKP2 variant D812N (in trans, one inherited from each of his unaffected parents). He had his first cardiac syncopal event (VT) at age 11 and was diagnosed at age 20. Baskin et al. (2013) found the variant in 2 ARVC patients tested in Canada. Bao et al. (2013) found it in 4 Chinese patients with ARVC. There is only very weak segregation data available: van Tintelen et al. (2006) saw it segregate in 2 affected family members. Palmisano et al. (2011) saw it segregate in an affected father and son. In total the variant has not been seen in more than 8500 presumably unaffected individuals, including 2000 controls and ~6500 individuals from population datasets. Dalal et al. (2006) did not find it in 200 controls (ancestry not specified); van Tintelen et al. (2006), 150 Caucasian controls; Wlodarska et al. (2008), 100 Caucasian controls; Fressart et al. (2010), 300 Caucasian controls; Cox et al. (2011), 200 Dutch Caucasian controls; Quarta et al. (2011), 300 ethnically-matched controls; Nakajima et al. (2012), 80 Japanese controls; Baskin et al. (2013), 427 controls; Bao et al. (2013), 300 Chinese(?) controls. It is not seen in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Chinese. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of March 27, 2014).

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