Submissions for variant NM_003001.5(SDHC):c.422_423insT (p.Lys141fs)

dbSNP: rs1672548902

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047447	SCV001211409	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2023-08-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 844567). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the SDHC protein in which other variant(s) (p.Leu158Pro) have been observed in individuals with SDHC-related conditions (PMID: 12807974). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This sequence change results in a frameshift in the SDHC gene (p.Lys141Asnfs*66). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the SDHC protein and extend the protein by 36 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency).
Myriad Genetics, Inc.	RCV003455196	SCV004189822	likely pathogenic	Paragangliomas 3	2023-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation.
Ambry Genetics	RCV004031473	SCV005020190	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The c.422_423insT variant, located in coding exon 6 of the SDHC gene, results from an insertion of one nucleotide at position 422, causing a translational frameshift with a predicted alternate stop codon (p.K141Nfs*66). This alteration occurs at the 3' terminus of theSDHC gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 36 amino acids. This frameshift impacts the last 29amino acids of the native protein. However, frameshifts are typically deleterious in nature, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.