rs200301019
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_003000.3(SDHB):āc.521T>Cā(p.Ile174Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,449,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I174V) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.521T>C | p.Ile174Thr | missense_variant | 5/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.467T>C | p.Ile156Thr | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.521T>C | p.Ile174Thr | missense_variant | 5/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD4 exome AF: 0.00000552 AC: 8AN: 1449274Hom.: 0 Cov.: 28 AF XY: 0.00000693 AC XY: 5AN XY: 721896
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 19, 2023 | This variant is present in population databases (rs200301019, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 174 of the SDHB protein (p.Ile174Thr). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 412477). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2021 | The p.I174T variant (also known as c.521T>C), located in coding exon 5 of the SDHB gene, results from a T to C substitution at nucleotide position 521. The isoleucine at codon 174 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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