ClinVar Miner

Submissions for variant NM_001164277.1(SLC37A4):c.1042_1043del (p.Leu348fs) (rs80356491)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723824 SCV000331530 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000007336 SCV000680381 pathogenic Glucose-6-phosphate transport defect 2017-11-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007336 SCV000697753 pathogenic Glucose-6-phosphate transport defect 2017-03-14 criteria provided, single submitter clinical testing Variant summary: The SLC37A4 c.1042_1043delCT (p.Leu348Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC37A4 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 24/103512 control chromosomes at a frequency of 0.0002319, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC37A4 variant (0.0012247). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic.The variant was identified in multiple affected individuals homozygously or in compound heterozygosity in patients with clinically and biochemically confirmed Glycogen Storage Disease Type 1b (GSD1b). Multiple family studies showed segregation of this variant with GSD1b (Veiga-de-Cunha_AJHG_1998; Hiraiwa_J. Biol. Chem.-1999). Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000601076 SCV000712814 pathogenic Glycogen storage disease 2017-01-24 criteria provided, single submitter clinical testing The p.Leu348ValfsX53 (NM_001164277.1 c.1042_1043delCT) variant in SLC37A4 (also referred to as c.1211delCT in the literature) has been reported in at least 3 ho mozygous and 10 compound heterozygous individuals with clinical features of Glyc ogen storage disease type I (GSDI) (Veiga da Cunha 1998, Janecke 1999, and Sante r 2000). This variant is reported as Pathogenic by three sources in ClinVar (Var iation ID#6926). This variant has also been identified in 13/57880 of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs80356491). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant is predicted to cause a frameshift, which alters the prote in?s amino acid sequence beginning at position 348 and leads to a premature term ination codon 53 amino acids downstream. This alteration is then predicted to le ad to a truncated or absent protein. Biallelic loss of function of the SLC37A4 gene has been associated with Glycogen storage disease type I (GSDI). In summary , the p.Leu348ValfsX53 variant in SLC37A4 meets criteria for pathogenic for GSDI in an autosomal recessive manner based upon its biallelic occurrence in patient s with this disease and predicted functional impact.
Ambry Genetics RCV000624535 SCV000741202 likely pathogenic Inborn genetic diseases 2015-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000007336 SCV000755870 pathogenic Glucose-6-phosphate transport defect 2020-01-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SLC37A4 gene (p.Leu348Valfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acids of the SLC37A4 protein. This variant is present in population databases (rs80356491, ExAC 0.07%). This variant has been reported as homozygous or in trans with other variants in several individuals affected with glycogen storage disease (PMID: 10923042, 15953877, 22899091, 26913919, 28224773). ClinVar contains an entry for this variant (Variation ID: 6926). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000723824 SCV001168625 pathogenic not provided 2018-10-31 criteria provided, single submitter clinical testing The c.1042_1043delCT variant in the SLC37A4 gene is a common pathogenic variant associated with glycogen storage disease type Ib; it has been reported previously (as c.1211_1212delCT using alternate nomenclature in some reports) in either the homozygous state or with a second variant in multiple unrelated affected individuals (Marcolongo et al., 1998; Veiga-da-Cunha et al., 1998; Han et al., 2005). This variant has also been reported in at least one individual reported to have a clinical diagnosis of glycogen storage disease type Ic (Janecke et al., 1999). The c.1042_1043delCT variant causes a frameshift starting with codon Leucine 348, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Leu348ValfsX53. This frameshift variant is predicted to result in protein truncation. The c.1042_1043delCT variant is observed in 57/274,352 (0.021%) alleles in large population cohorts and no individuals were homozygous (Lek et al., 2016). We interpret c.1042_1043delCT as a pathogenic variant.
Myriad Women's Health, Inc. RCV000007336 SCV001193826 pathogenic Glucose-6-phosphate transport defect 2019-12-19 criteria provided, single submitter clinical testing NM_001164277.1(SLC37A4):c.1042_1043delCT(L348Vfs*53, aka 1211delCT) is classified as pathogenic in the context of glycogen storage disease type Ib. Sources cited for classification include the following: PMID 9758626, 10923042 and 10940311. Classification of NM_001164277.1(SLC37A4):c.1042_1043delCT(L348Vfs*53, aka 1211delCT) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000007336 SCV000027534 pathogenic Glucose-6-phosphate transport defect 1999-03-01 no assertion criteria provided literature only
OMIM RCV000007337 SCV000027535 pathogenic Phosphate transport defect 1999-03-01 no assertion criteria provided literature only
GeneReviews RCV000007336 SCV000040885 pathogenic Glucose-6-phosphate transport defect 2016-08-25 no assertion criteria provided literature only

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