rs1060503756
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_003000.3(SDHB):āc.49A>Gā(p.Thr17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17I) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.49A>G | p.Thr17Ala | missense_variant | 1/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.49A>G | p.Thr17Ala | missense_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.49A>G | p.Thr17Ala | missense_variant | 1/8 | 1 | NM_003000.3 | P1 | |
SDHB | ENST00000466613.2 | n.61A>G | non_coding_transcript_exon_variant | 1/3 | 2 | ||||
SDHB | ENST00000485515.5 | n.37A>G | non_coding_transcript_exon_variant | 1/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460738Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726612
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152308Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2023 | Variant summary: SDHB c.49A>G (p.Thr17Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 242948 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49A>G has been reported in the literature as a VUS/likely benign variant in individuals affected with features of single pheochromocytoma and/or paraganglioma (example, PMID: 22293219, 30050099, 23404858, 31104306, 29386252, 26269449). These report(s) do not provide unequivocal conclusions about association of the variant with Pheochromocytoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 17 of the SDHB protein (p.Thr17Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 22293219, 26269449, 29386252, 30050099). ClinVar contains an entry for this variant (Variation ID: 412461). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of paraganglioma, but tumor studies in one individual implicated VHL as the causative locus and also did not find an elevated succinate: fumarate ratio (Domingues et al., 2012; Cascon et al., 2013; Andrews et al., 2018; Richter et al., 2019); This variant is associated with the following publications: (PMID: 29386252, 26269449, 26273102, 30050099, 23404858, 22293219, 31104306) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2023 | The p.T17A variant (also known as c.49A>G), located in coding exon 1 of the SDHB gene, results from an A to G substitution at nucleotide position 49. The threonine at codon 17 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals with paragangliomas and/or pheochromocytomas (Domingues R et al. J. Endocrinol. Invest. 2012 Dec;35:975-80; Cascón A et al. Endocr Relat Cancer, 2013 Jun;20:L1-6; Donato S et al. Endocrine, 2019 08;65:408-415; Richter S et al. Genet. Med., 2019 03;21:705-717). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This amino acid position is poorly conserved in available vertebrate species and alanine is the reference amino acid in many other vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at