chr1-161314406-A-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001407119.1(SDHC):c.-560A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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 Pathogenic (★★).
Frequency
Consequence
NM_001407119.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHC | NM_003001.5 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 6 | ENST00000367975.7 | NP_002992.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461868Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Pathogenic:1
This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with SDHC-related conditions (PMID: 11062460, 16249420, 19351833, 19454582, 22351710, 22517554, 23282968, 29386252). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 653751). For these reasons, this variant has been classified as Pathogenic. -
Paragangliomas 3 Pathogenic:1
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30201732, 30877234, 16249420, 11062460, 25720320]. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the SDHC gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in multiple individuals with features consistent with SDHC-related paraganglioma-pheochromocytoma syndrome (Andrews KA et al. J Med Genet, 2018 Jun;55:384-394; Williams et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at