Submissions for variant NM_002180.2(IGHMBP2):c.1669C>G (p.Pro557Ala) (rs7122089)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517070	SCV000613765	uncertain significance	not specified	2017-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000766761	SCV000618154	uncertain significance	not provided	2018-12-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the IGHMBP2 gene. The P557A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P557A variant is observed in 30/10276 (0.3%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P557A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001088877	SCV000764352	likely benign	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2019-12-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001112397	SCV001270054	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1	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.