rs1553261757

Positions:

• chr1-161323610-GCAGAC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003001.5(SDHC):​c.21-3_22del variant causes a splice acceptor, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHC NM_003001.5 splice_acceptor, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.83

Genes affected

SDHC (HGNC:10682): (succinate dehydrogenase complex subunit C) This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10980392 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161323610-GCAGAC-G is Pathogenic according to our data. Variant chr1-161323610-GCAGAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517289.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5	c.21-3_22del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.21-3_22del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/6	1	NM_003001.5	ENSP00000356953	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2017

The c.21-3_22del variant in SDHC has not been previously reported in individuals with SDHC-related cancers (hereditary paraganglioma-pheochromocytoma syndrome) and was absent from large population studies. This variant is a deletion that sp ans the invariant region (+/- 1,2) of the splice consensus sequence and is predi cted to cause altered splicing leading to an abnormal or absent protein. A signi ficant fraction of pathogenic SDHC variants are loss of function and splice vari ants, suggesting that the c.21-3_22del variant is disease causing. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the c.21-3_22del variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553261757; hg19: chr1-161293400;