ClinVar Miner

Submissions for variant NM_001289808.2(CRYAB):c.116C>T (p.Pro39Leu) (rs149787233)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154694 SCV000204373 uncertain significance not specified 2013-04-12 criteria provided, single submitter clinical testing The Pro39Leu variant in CRYAB has not been reported in individuals with cardiomy opathy, but has been identified in 5/8594 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1497872 33). Computational analyses (biochemical amino acid properties, conservation, Al ignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an im pact to the protein. Additional information is needed to fully assess the clinic al significance of this variant.
Illumina Clinical Services Laboratory,Illumina RCV000335745 SCV000367274 uncertain significance Fatal infantile hypertonic myofibrillar myopathy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000371984 SCV000367275 benign Alpha-B crystallinopathy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000296232 SCV000367276 benign Cataract 16, multiple types 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genetic Services Laboratory, University of Chicago RCV000154694 SCV000594225 uncertain significance not specified 2016-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617272 SCV000735832 uncertain significance Cardiovascular phenotype 2019-01-21 criteria provided, single submitter clinical testing The p.P39L variant (also known as c.116C>T), located in coding exon 1 of the CRYAB gene, results from a C to T substitution at nucleotide position 116. The proline at codon 39 is replaced by leucine, an amino acid with similar properties. This alteration was reported in one individual with left ventricular non-compaction (LVNC) who also had a variant in another cardiac-related gene (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000655018 SCV000776938 uncertain significance Dilated cardiomyopathy 1II 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 39 of the CRYAB protein (p.Pro39Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs149787233, ExAC 0.06%). This variant has not been reported in the literature in individuals with CRYAB-related disease. ClinVar contains an entry for this variant (Variation ID: 178013). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
GeneDx RCV001550214 SCV001770510 uncertain significance not provided 2020-02-14 criteria provided, single submitter clinical testing Previously reported in an individual with left ventricular non-compaction who also harbored variants in the LMNA and MYLK2 genes (Miszalski-Jamka et al., 2017); 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: 28798025)

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