rs541660851
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_003001.5(SDHC):c.436C>A(p.Pro146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146L) has been classified as Uncertain significance.
Frequency
Consequence
NM_003001.5 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 |
---|---|---|---|---|---|---|---|
SDHC | NM_003001.5 | c.436C>A | p.Pro146Thr | missense_variant | 6/6 | ENST00000367975.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHC | ENST00000367975.7 | c.436C>A | p.Pro146Thr | missense_variant | 6/6 | 1 | NM_003001.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000671 AC: 1AN: 149030Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461386Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726996
GnomAD4 genome ? AF: 0.00000671 AC: 1AN: 149030Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 72420
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1854336:Paragangliomas 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2022 | - - |
Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 146 of the SDHC protein (p.Pro146Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 142904). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 | Sep 06, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2022 | The p.P146T variant (also known as c.436C>A), located in coding exon 6 of the SDHC gene, results from a C to A substitution at nucleotide position 436. The proline at codon 146 is replaced by threonine, an amino acid with highly 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. - |
Paragangliomas 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 06, 2022 | The SDHC c.436C>A (p.Pro146Thr) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at