ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1540G>A (p.Glu514Lys) (rs137852665)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235071 SCV000292361 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2015-08-18 criteria provided, single submitter research This variant has been previously reported as disease-causing and was identified with another variant in this gene, in an individual with congenital hypotonia and respiratory involvement.
GeneDx RCV000235520 SCV000293147 pathogenic not provided 2015-09-23 criteria provided, single submitter clinical testing The E514K variant has been previously reported in the homozygous state in a patient with SMARD1 and in the heterozygous state in a SMARD1 patient whom also had a second IGHMBP2 mutation (Grohmann et al., 2001; Grohmann et al., 2003; Diers et al., 2005; Gonzaga-Jauregui et al., 2015). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E514K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, E514K is interpreted to be a pathogenic variant
Invitae RCV000693255 SCV000821115 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 514 of the IGHMBP2 protein (p.Glu514Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs137852665, ExAC 0.006%). This variant has been reported to segregate with disease in two families affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 11528396, 15503272) and reported as homozygous or in combination with another IGHMBP2 variant in several individuals affected with SMARD1 (PMID: 14681881, 26257172). ClinVar contains an entry for this variant (Variation ID: 9112). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009682 SCV000029900 pathogenic Werdnig-Hoffmann disease 2001-09-01 no assertion criteria provided literature only

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