rs200896502
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_003000.3(SDHB):āc.739A>Gā(p.Met247Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M247I) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.739A>G | p.Met247Val | missense_variant | 7/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.685A>G | p.Met229Val | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.739A>G | p.Met247Val | missense_variant | 7/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251440Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461736Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727190
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 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; Observed in an individual with vaginal fusocellular sarcoma and endometrial adenocarcinoma (de Angelis de Carvalho et al., 2020); This variant is associated with the following publications: (PMID: 32659967) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | SDHB: PM2 - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2024 | The p.M247V variant (also known as c.739A>G), located in coding exon 7 of the SDHB gene, results from an A to G substitution at nucleotide position 739. The methionine at codon 247 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was identified in a female patient diagnosed with high-grade vaginal fusocellular sarcoma and endometrial adenocarcinoma (de Angelis de Carvalho N et al. Cancers (Basel), 2020 Jul;12:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 10, 2021 | - - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the SDHB protein (p.Met247Val). This variant is present in population databases (rs200896502, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 32659967). ClinVar contains an entry for this variant (Variation ID: 459169). 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 expected to disrupt SDHB protein function with a positive predictive value of 80%. 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. - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 26, 2023 | - - |
SDHB-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 14, 2023 | The SDHB c.739A>G variant is predicted to result in the amino acid substitution p.Met247Val. This variant has been reported in an individual with Lynch syndrome and sarcomas (Table S1, de Angelis de Carvalho et al. 2020. PubMed ID: 32659967). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-17349129-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/459169/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at