5-218356-A-ATGTCGGGGGTCCGGGGCC

Variant names:

• chr5-218356-A-ATGTCGGGGGTCCGGGGCC
• rs1734496050
• NM_004168.4:c.7_24dupGGGGTCCGGGGCCTGTCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004168.4(SDHA):​c.7_24dupGGGGTCCGGGGCCTGTCG​(p.Gly3_Ser8dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: SDHA NM_004168.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004168.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.7_24dupGGGGTCCGGGGCCTGTCG	p.Gly3_Ser8dup	conservative_inframe_insertion	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-292_-275dupGGCCCCGGACCCCCGACA		upstream_gene_variant		ENST00000296824.4	NP_660308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.7_24dupGGGGTCCGGGGCCTGTCG	p.Gly3_Ser8dup	conservative_inframe_insertion	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.7_24dupGGGGTCCGGGGCCTGTCG		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-292_-275dupGGCCCCGGACCCCCGACA		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

May 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 SDHA-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.7_24dup, results in the insertion of 6 amino acid(s) of the SDHA protein (p.Gly3_Ser8dup), but otherwise preserves the integrity of the reading frame. -

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: rs1734496050; hg19: chr5-218471;