Submissions for variant NM_001289808.2(CRYAB):c.343del (p.Ser115fs)

gnomAD frequency: 0.00001  dbSNP: rs281865142

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183328	SCV000235760	pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 61 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect as induced pluripotent stem cells (iPSC) derived from fibroblasts from an infant with myofibrillar myopathy showed that this variant causes protein insolubility, resulting in the loss of alpha-B-crystallin protein expression in iPSC-derived skeletal myotubes and cardiomyocytes (Mitzelfelt et al., 2016); Reported in ClinVar (ClinVar Variant ID# 38963; Landrum et al., 2016); While other truncating variants in the CRYAB gene have been reported in HGMD in association with autosomal recessive infantile myofibrillar myopathy (Stenson et al., 2014), only one truncating variant has been previously reported in association with autosomal dominant cardiomyopathy (Jensen et al. 2013).; This variant is associated with the following publications: (PMID: 21130652, 27226619, 31534214)
Invitae	RCV000694268	SCV000822704	pathogenic	Dilated cardiomyopathy 1II	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser115Profs*14) in the CRYAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the CRYAB protein. This variant is present in population databases (rs281865142, gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive myofibrillar myopathy (PMID: 21130652, 27226619). ClinVar contains an entry for this variant (Variation ID: 38963). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRYAB function (PMID: 21130652, 27226619). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000183328	SCV000862831	likely pathogenic	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000183328	SCV002019739	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504850	SCV002815440	pathogenic	Myofibrillar myopathy 2; Cataract 16 multiple types; Fatal infantile hypertonic myofibrillar myopathy; Dilated cardiomyopathy 1II	2021-08-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018700	SCV004851127	uncertain significance	Cardiovascular phenotype	2021-12-03	criteria provided, single submitter	clinical testing	The c.343delT (p.S115Pfs*14) alteration, located in exon 3 (coding exon 3) of the CRYAB gene, consists of a deletion of one nucleotide at position 343, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneReviews	RCV000032215	SCV000055817	not provided	Myofibrillar myopathy 2		no assertion provided	literature only