ClinVar Miner

Submissions for variant NM_001289808.2(CRYAB):c.460G>A (p.Gly154Ser) (rs150516929)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037217 SCV000060874 uncertain significance not specified 2015-03-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gly154Ser var iant in CRYAB has been reported in 2 individuals with mild DCM (Inagaki 2006, Pi lotto 2006) and in 2 individuals with myopathy (Reilich 2010, Semmler 2014). Add itionally, one unpublished study detected this variant in 8 individuals with HCM (Sriram 2007; conference abstract). This variant has also been identified by ou r laboratory in 3 individuals with HCM, 2 individuals with DCM, and 1 individual with RV dilation and ventricular tachycardia. However, one of the individuals w ith HCM carried a variant in another gene that is sufficient to explain their di sease. This variant has been identified in 0.1% (85/66736) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs150516929). In vitro functional studies provide some evidence that the p.G ly154Ser variant may impact protein function (Inagaki 2006, Reilich 2010, Ragu 2 013). However, these types of assays may not accurately represent biological fun ction. In summary, while the clinical significance of the p.Gly154Ser variant is uncertain, the wide range of phenotypes of individuals with this variant and it s frequency in the general population suggest that it is more likely to be benig n.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000658624 SCV000228972 uncertain significance not provided 2014-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000658624 SCV000235757 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CRYAB gene. The G154S variant has previously been published in association with dilated cardiomyopathy and myopathy (Pilotto et al., 2006; Reilich et al., 2010; Vattemi et al., 2011; Semmler et al., 2014; Ma et al., 2015). However, this variant was also identified in the asymptomatic son of one proband (Semmler et al., 2014) and in the unaffected father of an unrelated proband, while it was absent from this proband's affected mother, demonstrating lack of segregation with disease in this family (Ma et al., 2015). Functional studies suggest that G154S impacts normal protein function in vitro due to the formation of aggregates within G154S transfected cells (Raju et al., 2013). However, Huang et al., (2016) observed no significant difference between peak sodium current density when G154S was compared to wild-type. The G154S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. The G154S variant was observed in 192/126,712 (0.15%) alleles from individuals of European (Non-Finnish) background in large population cohorts (Lek et al., 2016). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.The G154S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Functional studies conducted by Raju et al. (2013) suggest that G154S impacts normal protein function in vitro due to the formation of aggregates within G154S transfected cells. Through additional in vitro experimentation, Gerasimovich et al. (2017) observed that many properties of G154S are very similar to those of wild-type, yet G154S is less thermostable than wild-type and possesses lower chaperone-like activity. However, Huang et al., (2016) observed no significant difference between peak sodium current density when G154S was compared to wild-type.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000297606 SCV000367259 likely benign Cataract 16, multiple types 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000352488 SCV000367260 likely benign Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000398508 SCV000367261 likely benign Fatal infantile hypertonic myofibrillar myopathy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000034839 SCV000563211 likely benign Dilated cardiomyopathy 1II 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620796 SCV000735430 likely benign Cardiovascular phenotype 2019-03-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Does not segregate with disease in family study (genes with incomplete penetrance);Other strong data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658624 SCV000780406 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852658 SCV000995364 likely benign Congestive heart failure; Hypertrophic cardiomyopathy 2019-04-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037217 SCV001159276 likely benign not specified 2019-03-24 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170406 SCV001332983 benign Cardiomyopathy 2018-03-16 criteria provided, single submitter clinical testing
OMIM RCV000034839 SCV000058409 pathogenic Dilated cardiomyopathy 1II 2006-08-11 no assertion criteria provided literature only
Blueprint Genetics RCV000157153 SCV000206876 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-10-27 no assertion criteria provided clinical testing
Eye Genetics Research Group,Children's Medical Research Institute RCV000203359 SCV000256002 uncertain significance Congenital cataract 2015-01-09 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000658624 SCV000925047 uncertain significance not provided 2017-03-31 no assertion criteria provided provider interpretation Given the high prevalence of this variant in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been reported multiple times in the literature associated with dilated cardiomyopathy, myofibrillar myopathy and cataracts. However, recently published control population data indicates that this variant is common in healthy people (MAF 0.15%) and so was likely found by chance in these reports. The variant has been seen in at least 21 unrelated cases of dilated cardiomyopathy, myofibrillar myopathy and cataracts (not including this patient's family). There is little segregation data, which is weak. At least 5 of the 17 probands sequenced at clinical labs had another pathogenic or likely pathogenic variant in another gene. This variant is present in ClinVar, with conflicting interpretations of pathogenicity. Emory and GeneDx classify this as a variant of uncertain significance. The Laboratory for Molecular Medicine classifies this as a variant of uncertain significance, likely benign. The Illumina Clinical Services Laboratory classifies it as likely benign. This variant was identified in a 48 year old patient with DCM. Had a father with heart failure dx at 60 and died at 80. Paternal history of ocular problems, not otherwise specified (Pilotto et al 2006). This variant was found in a 70 year old male patient with distal myopathy, with onset at 60 years. The patient's maternal grandmother also had a cardiomyopathy. The patient also had coronary artery disease and intermittent atrial fibrillation. ECG showed right bundle branch block and echocardiogram showed a dilated right atrium. No eye findings other than very mild, age-appropriate cataracts. Sequencing of other genes associated with myofibrillar myopathy was negative: DES, TTID, LDB3 and FLNC (Reilich et al 2010). Vattemi and colleagues (2011) found this variant in 1 out of 21 patients with myofibrillar myopathy. Semmler and colleagues (2014) found this variant in a patient who presented at 69 years of age with several episodes of rhabdomyolitis, exercise intolerance, fatigue and respiratory insufficiency. His 42 year old son also had this variant and did not have any symptoms except for a mild elevation in CK. In terms of functional data, Raju et al demonstrated that HeLa cells transfected with this variant showed a moderate amount of aggregation, a phenomenon common in myofibrillar myopathy. Huang et al 2016 found that the G154S variant did not affect beta-crystallin's capability in enhancing the sodium current density. According to the test report, "the G154S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties." The glycine at codon 154 is moderately conserved across species, as are neighboring amino acids. The variant was reported online in 223 of 123,132 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 169 of 55,857 individuals of European (non-Finnish) descent (MAF=0.15%), 31 out of 11,150 individuals of Finnish descent, 17 out of 16,791 individuals of Latino descent, 4 out of 2,743 individuals of "other" descent, 1 out of 7,652 individuals of African descent and 1 out of 4,925 individuals of Ashkenazi Jewish descent. 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). This variant was absent from 200 controls (Pilotto et al 2013)

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