rs72552293
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_015141.4(GPD1L):c.370A>G(p.Ile124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,054 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I124M) has been classified as Uncertain significance.
Frequency
Consequence
NM_015141.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPD1L | NM_015141.4 | c.370A>G | p.Ile124Val | missense_variant | 4/8 | ENST00000282541.10 | |
GPD1L | XM_006713068.3 | c.229A>G | p.Ile77Val | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPD1L | ENST00000282541.10 | c.370A>G | p.Ile124Val | missense_variant | 4/8 | 1 | NM_015141.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00274 AC: 417AN: 152138Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00251 AC: 630AN: 251360Hom.: 7 AF XY: 0.00244 AC XY: 332AN XY: 135844
GnomAD4 exome AF: 0.00165 AC: 2412AN: 1461798Hom.: 9 Cov.: 32 AF XY: 0.00168 AC XY: 1219AN XY: 727210
GnomAD4 genome ? AF: 0.00274 AC: 417AN: 152256Hom.: 4 Cov.: 32 AF XY: 0.00341 AC XY: 254AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 23, 2019 | This variant is associated with the following publications: (PMID: 22995991, 19606473, 29077258, 17967976, 24055113, 23465283, 21215473, 25395996, 25998140, 23295036, 24715918, 28837624, 30615648, 15140536, 31019283, 31043699, 30847666) - |
Brugada syndrome 2 Pathogenic:1Uncertain:1Benign:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 13, 2007 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 19, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.2% (82/6614) Finnish chromosomes - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 25, 2018 | Variant summary: GPD1L c.370A>G (p.Ile124Val) results in a conservative amino acid change located in the N-terminal of the Glycerol-3-phosphate dehydrogenase, NAD-dependent domain (IPR011128) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 277792 control chromosomes in the gnomAD database and publications, including 7 homozygotes. The observed variant frequency is approximately 289-fold of the estimated maximal expected allele frequency for a pathogenic variant in GPD1L causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. The variant, c.370A>G, has been reported in the literature in individuals affected with SIDS, sudden death, and atrial fibrillation (VanNorstrand_2007, Skinner_2014, Husser_2017). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (VanNorstrand_2007). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
GPD1L-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
SUDDEN INFANT DEATH SYNDROME Benign:1
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Long QT syndrome;C0949658:Primary familial hypertrophic cardiomyopathy Benign:1
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 04, 2014 | - - |
Brugada syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Mar 12, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at