rs80356491
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001164279.2(SLC37A4):โc.823_824delโ(p.Leu275ValfsTer53) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,612,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (โ โ ). Synonymous variant affecting the same amino acid position (i.e. L275L) has been classified as Likely benign.
Frequency
Consequence
NM_001164279.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164277.2 | c.1042_1043del | p.Leu348ValfsTer53 | frameshift_variant | 10/11 | ENST00000642844.3 | |
SLC37A4 | NM_001164279.2 | c.823_824del | p.Leu275ValfsTer53 | frameshift_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.1042_1043del | p.Leu348ValfsTer53 | frameshift_variant | 9/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000167 AC: 41AN: 246170Hom.: 0 AF XY: 0.000172 AC XY: 23AN XY: 133586
GnomAD4 exome AF: 0.000175 AC: 256AN: 1460488Hom.: 0 AF XY: 0.000182 AC XY: 132AN XY: 726420
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74486
ClinVar
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:10Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Leu348Valfs*53) in the SLC37A4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the SLC37A4 protein. This variant is present in population databases (rs80356491, gnomAD 0.04%). This premature translational stop signal has been observed in individuals 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 or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Nov 08, 2022 | PVS1, PS4, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Nov 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 26, 2021 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong, PP1 supporting, PP4 supporting - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jul 03, 2021 | A homozygous 2 base pair deletion in exon 11 of the SLC37A4 gene that results in frameshift and premature truncation of the protein 53 amino acids downstream to codon 370. The observed variant c.1108_1109del (p.Leu370ValfsTer53) has not been reported in the 1000 genomes and has a MAF of 0.03% in the gnomAD databases. The in silico prediction of the variant are damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic variant. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2024 | Frameshift variant predicted to result in abnormal protein length as the last 82 amino acids are replaced with 52 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 18437526, 30609409, 31508908, 37147621, 34946936, 34775139, 25971127, 15953877, 9758626, 9781688, 32005221, 31536830, 34426522, 34093448, 31589614, 33977030, 35433171, 35822097, 38087503, 37275680, 38531056, 35620924, 38605407, 36964972, 36039216, 37779861, 10323254) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Phosphate transport defect Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006926 / PMID: 9781688). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Congenital disorder of glycosylation, type IIw Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Aug 10, 2022 | The c.1042_1043del;p.(Leu348Valfs*53) is a null frameshift variant (NMD) in the SLC37A4 gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD); it is present in a relevant exon to the transcript, and disrupts >10% of the protein product โ PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 6926; PMID: 20301489; 28224773; 26913919; 22899091; 15953877) - PS4. The variant is present at low allele frequencies population databases (rs80356491 โ gnomAD 0.002562%; ABraOM 0.002562 frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Leu348Valfs*53) was detected in trans with a pathogenic variant (PMID: 22899091; 26913919; 28224773) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2015 | - - |
Glycogen storage disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | 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. - |
Glycogen storage disease, type I Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Breakthrough Genomics, Breakthrough Genomics | - | The SLC37A4 c.1042_1043delCT variant (also referred to as c.1211delCT in the literature) was previously reported in homozygous or compound heterozygous state in various ethnic individuals affected with glycogen storage disease and was classified as pathogenic variant [PMID: 9758626, 10026167, 10923042, 10323254, 15953877, 22899091, 26913919, 28224773]. Additionally, this variant was found to be segregated with GSDI disease phenotype in multiple family studies [PMID: 9758626, 10026167]. - |
Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at