ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.2922T>G (p.Asp974Glu) (rs147674615)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000712265 SCV000226265 uncertain significance not provided 2014-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334797 SCV000373815 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1 2017-04-27 criteria provided, single submitter clinical testing The IGHMBP2 c.2922T>G (p.Asp974Glu) missense variant has been reported in one study in which it is found in a compound heterozygous state in one individual with spinal muscular atrophy (Grohmann et al. 2003). Control data are unavailable for this variant, which it is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Asp974Glu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for spinal muscular atrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001084583 SCV000642357 likely benign Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2020-12-04 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV001706121 SCV000842711 likely benign not specified 2020-04-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000712265 SCV000884027 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing The p.Asp974Glu variant (rs147674615) was reported in one patient with spinal muscular atrophy who carried a second in-frame deletion variant in IGHMBP2 (Grohmann 2003). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.2 percent in the European Non-Finnish population (identified on 229 out of 124,638 chromosomes, including 1 homozygote) and has been reported to the ClinVar database (Variation ID: 194494). The aspartic acid at position 974 is moderately conserved considering 11 species (Alamut v2.11) and computational analyses of the effects of the p.Asp974Glu variant on protein structure and function provide conflicting results (SIFT: tolerated, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Asp974Glu variant with certainty.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173329 SCV001336417 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Baylor Genetics RCV001336444 SCV001529829 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2S 2018-07-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000712265 SCV001552573 likely benign not provided no assertion criteria provided clinical testing The IGHMBP2 p.Asp974Glu variant was identified 1 of 58 proband chromosomes (frequency: 0.017) from an infant with distal spinal muscular atrophy with respiratory distress type 1 (SMARD1) who carried another variant of uncertain significance in the IGHMBP2 gene (Grohmann_2003_PMID: 14681881). The variant was identified in dbSNP (ID: rs147674615) and ClinVar (classified as uncertain significance by Athena diagnostics, ARUP laboratories, EGL Diagnostics, and Illuminal, and as likely benign by Invitae). The variant was identified in control databases in 304 of 278604 chromosomes (1 homozygous) at a frequency of 0.001091 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 239 of 126884 chromosomes (freq: 0.001884), Other in 12 of 7070 chromosomes (freq: 0.001697), African in 21 of 24426 chromosomes (freq: 0.00086), Latino in 28 of 35132 chromosomes (freq: 0.000797), European (Finnish) in 3 of 24636 chromosomes (freq: 0.000122) and South Asian in 1 of 30452 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Asp974 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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