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

gnomAD frequency: 0.00088  dbSNP: rs150516929

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 Add itionally, one unpublished study detected this variant in 8 individuals with HCM (Sriram 2007; conference abstract).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.
Eurofins Ntd Llc (ga)	RCV000658624	SCV000228972	uncertain significance	not provided	2014-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000658624	SCV000235757	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	Reported in association with both DCM, myopathy, and sudden cardiac death (SCD) (PMID: 16793013, 20171888, 22106715, 25208129, 26694549, 35087879); Functional studies suggest the presence of this variant may alter protein interactions under various experimental conditions; however, it is not known whether these findings are biological or clinically relevant in vivo (PMID: 23194663, 26961874, 28919577, 34983005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21920752, 27896284, 22995991, 23299917, 22106715, 26210153, 26961874, 24694370, 26694549, 20171888, 25961584, 21423662, 28518168, 28919577, 32171521, 32955210, 30325262, 29915098, 37511242, 25208129, 16793013, 23194663, 34983005, 35087879)
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000352488	SCV000367260	likely benign	Myofibrillar Myopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034839	SCV000563211	likely benign	Dilated cardiomyopathy 1II	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620796	SCV000735430	likely benign	Cardiovascular phenotype	2019-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000658624	SCV000780406	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	CRYAB: BP4
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	RCV000658624	SCV001159276	likely benign	not provided	2021-01-12	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
Mayo Clinic Laboratories, Mayo Clinic	RCV000658624	SCV004226246	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037217	SCV005203690	likely benign	not specified	2024-07-30	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	Developmental 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)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000658624	SCV001742976	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037217	SCV001923745	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000658624	SCV001930845	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658624	SCV001971884	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000658624	SCV002037078	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914912	SCV004739171	likely benign	CRYAB-related disorder	2021-05-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).