Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV002493831 | SCV002787159 | uncertain significance | Autosomal dominant palmoplantar keratoderma and congenital alopecia; Atrioventricular septal defect and common atrioventricular junction; Craniometaphyseal dysplasia, autosomal recessive; Hypoplastic left heart syndrome 1; Oculodentodigital dysplasia, autosomal recessive; Syndactyly type 3; Oculodentodigital dysplasia; Erythrokeratodermia variabilis et progressiva 3 | 2022-03-02 | criteria provided, single submitter | clinical testing | |
| Breakthrough Genomics, |
RCV001357947 | SCV005189221 | uncertain significance | not provided | criteria provided, single submitter | not provided | ||
| Department of Pathology and Laboratory Medicine, |
RCV001357947 | SCV001553560 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The GJA1 p.Ala311Valfs*37 variant was identified in dbSNP (ID: rs778110855) and Cosmic but was not identified in ClinVar or LOVD 3.0. The variant was also identified in control databases in 20 of 278960 chromosomes at a frequency of 0.000072 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 10 of 24210 chromosomes (freq: 0.000413), European (non-Finnish) in 9 of 127046 chromosomes (freq: 0.000071) and African in 1 of 24558 chromosomes (freq: 0.000041), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Other, and South Asian populations. The p.Ala311Valfs*37 variant was identified in 1/10 patients with nonfamilial, lone atrial fibrillation as a somatic variant in atrial tissue but was not found in lymphocytes. Protien trafficking and electrophysiological studies of the mutant protein demonstrated intracellular retention and lack of electrical coupling compared to wildtype (Thibodeau_2010_PMID:20606116). The c.932del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 311 and leads to a premature stop codon 37 basepairs downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. However, the role of loss of function variants of the GJA1 gene in disease is currently unclear. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |