ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.623G>A (p.Arg208His) (rs111840209)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV000681638 SCV000809084 uncertain significance GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Infantile GM1 gangliosidosis 2018-04-20 criteria provided, single submitter clinical testing
Invitae RCV000876207 SCV001018750 likely benign Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001145887 SCV001306595 uncertain significance Mucopolysaccharidosis, MPS-IV-B 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, 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.
Illumina Clinical Services Laboratory,Illumina RCV001148903 SCV001309824 uncertain significance GM1 gangliosidosis 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, 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354677 SCV001549353 uncertain significance not provided no assertion criteria provided clinical testing The GLB1 p.Arg256His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs111840209), ClinVar (classified as a VUS by Mayo Clinic Genetic Testing Laboratories for Infantile GM1 gangliosidosis, GM1 gangliosidosis type 2 and Gangliosidosis GM1 type 3) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 337 of 280546 chromosomes (1 homozygous) at a frequency of 0.001201 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 133 of 25036 chromosomes (freq: 0.005312), Other in 12 of 7134 chromosomes (freq: 0.001682), European (non-Finnish) in 190 of 128374 chromosomes (freq: 0.00148) and African in 1 of 24182 chromosomes (freq: 0.000041), Latino in 1 of 35346 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Arg256 residue is not 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. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001354677 SCV001797580 likely benign not provided no assertion criteria provided clinical testing

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