ClinVar Miner

Submissions for variant NM_001199973.2(RPL36A-HNRNPH2):c.300+2608GA[2] (rs398123198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000236755 SCV000110103 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000236755 SCV000292562 pathogenic not provided 2015-09-21 criteria provided, single submitter clinical testing The c.1033_1034delTC mutation in the GLA gene has been reported previously in several unrelated males with Fabry disease and significantly reduced a-galactosidase activity (Germain et al., 1996; Pereira et al., 2007; Tsukimura et al., 2014). The deletion causes a frameshift starting with codon Serine 345, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Ser345ArgfsX29. This mutation is predicted to cause loss of normal protein function through protein truncation. This result is expected to be consistent with a diagnosis of Fabry disease
Integrated Genetics/Laboratory Corporation of America RCV000078263 SCV000695728 pathogenic Fabry disease 2016-06-03 criteria provided, single submitter clinical testing Variant summary: The GLA c.1033_1034delTC (p.Ser345Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87610 control chromosomes while it was reported in several Fabry patients indicating pathogenicity. GLA activity, GLA protein levels were severely decreased in affected carriers with Lyso-Gb3 being elevated further supporting pathogenicity. Additionally, a clinical diagnostic laboratory classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000078263 SCV001232317 pathogenic Fabry disease 2019-12-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GLA gene (p.Ser345Argfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acids of the GLA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Fabry disease (PMID: 8931708, 23935525). This variant is also known as L344-X28-Stop and c.1029-1030delTC in the literature. ClinVar contains an entry for this variant (Variation ID: 92538). This variant disrupts the C-terminus of the GLA protein. Other variant(s) that disrupt this region (p.Val376Profs*10) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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