Submissions for variant NM_000742.4(CHRNA2):c.1123C>G (p.Pro375Ala)

gnomAD frequency: 0.00004  dbSNP: rs746613509

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186875	SCV000240446	uncertain significance	not provided	2018-08-06	criteria provided, single submitter	clinical testing	p.Pro375Ala (CCC>GCC): c.1123 C>G in exon 6 of the CHRNA2 gene (NM_000742.3). The Pro375Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant alters a position that is not highly conserved, and it does not occur within the transmembrane region of the protein where pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). Although Proline and Alanine are both uncharged, non-polar amino acids, the loss of a bulky Proline residue may alter the secondary structure of the protein. Multiple in silico algorithms predict that Pro375Ala is damaging to the structure/function of the protein. The variant is found in EPILEPSY panel(s).
Illumina Laboratory Services, Illumina	RCV001159829	SCV001321572	likely benign	Autosomal dominant nocturnal frontal lobe epilepsy 4	2018-01-13	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV001852441	SCV002141267	likely benign	Autosomal dominant nocturnal frontal lobe epilepsy	2023-11-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003243007	SCV003950943	uncertain significance	Inborn genetic diseases	2023-05-31	criteria provided, single submitter	clinical testing	The c.1123C>G (p.P375A) alteration is located in exon 6 (coding exon 5) of the CHRNA2 gene. This alteration results from a C to G substitution at nucleotide position 1123, causing the proline (P) at amino acid position 375 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.