Submissions for variant NM_001289808.2(CRYAB):c.32G>A (p.Arg11His)

gnomAD frequency: 0.00004  dbSNP: rs782809283

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789399	SCV001244993	uncertain significance	Cataract 16 multiple types	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with dominant cataracts (MIM#613763) (PMID: 31239701, 16505043). LoF is a speculated mechanism for other conditions (DECIPHER). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with both dominant and recessive cataract 16, multiple types (MIM#613763) and dominant myofibrillar myopathy 2 (MIM#608810). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a condition (8 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele: 7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by two in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated Crystallin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in one family with autosomal dominant congenital nuclear cataract (PMID: 19597569). This variant has been listed as a VUS in a hypertrophic cardiomyopathy cohort (PMID: 30531895). This variant has also been reported as likely pathogenic and VUS in ClinVar. (SP) 0903 - This variant has limited evidence for segregation with disease in one family with autosomal dominant congenital nuclear cataract (PMID: 19597569). (SP) 1010 - Functional evidence for this variant is inconclusive. Functional studies showed the mutant protein altered protein structure and activity, promoted apoptosis (PMID: 21087083), showed moderate number of cells with aggregates (PMID: 23194663) and formed smaller oligomers than WT protein (PMID: 32533979). However, mutant protein did not affect the capability of alphaB-crystalllin in enhacing the sodium current density (PMID: 26961874). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089962	SCV001561066	uncertain significance	Dilated cardiomyopathy 1II	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 11 of the CRYAB protein (p.Arg11His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cataracts and/or dilated cardiomyopathy (PMID: 19597569, 32573669). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 870393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CRYAB function (PMID: 21087083, 23194663). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg11 amino acid residue in CRYAB. Other variant(s) that disrupt this residue have been observed in individuals with CRYAB-related conditions (PMID: 26402864), which suggests that this may be a clinically significant amino acid residue. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV001784639	SCV002503025	uncertain significance	not provided	2021-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004031218	SCV005017975	uncertain significance	Cardiovascular phenotype	2023-09-15	criteria provided, single submitter	clinical testing	The p.R11H variant (also known as c.32G>A), located in coding exon 1 of the CRYAB gene, results from a G to A substitution at nucleotide position 32. The arginine at codon 11 is replaced by histidine, an amino acid with highly similar properties. This variant segregated with autosomal dominant congenital cataract phenotype in one family, and has been detected in an infant with dilated cardiomyopathy (Chen Q et al. Mol Vis, 2009 Jul;15:1359-65; Lunke, S et al. JAMA. 2020 Jun;323(24):2503-2511). Functional studies of this variant indicate it may impact protein function; however, some results are conflicting and the physiological relevance of the findings is unclear (Chen Q et al. Biol Chem, 2010 Dec;391:1391-400; Raju I et al. Biochem Biophys Res Commun, 2013 Jan;430:107-12; Muranova LK et al. Exp Eye Res, 2020 Aug;197:108091). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587042	SCV005077517	uncertain significance	not specified	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: CRYAB c.32G>A (p.Arg11His) results in a non-conservative amino acid change located in the Alpha-crystallin, N-terminal domain (IPR003090) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 1598882 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.32G>A has been reported in the literature in individuals affected with autosomal dominant Cataract 16 and was shown to segregate with disease in one family (e.g., Chen_2009), as well as one individual with cardiomyopathy (e.g., Lunke_2020), although no co-segregation data was provided. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant leads to an increased number of cells with protein aggregates, although conflicting findings were reported on the effect of the variant on enhancing apoptosis (e.g., Chen_2010, Raju_2012). These studies therefore do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 21087083, 19597569, 32573669, 23194663). ClinVar contains an entry for this variant (Variation ID: 870393). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.