rs750865703

Variant names:

• chr5-254482-C-CT
• rs750865703
• NM_004168.4:c.1885dupT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_004168.4(SDHA):​c.1885dupT​(p.Tyr629LeufsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.14

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0546 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-254482-C-CT is Pathogenic according to our data. Variant chr5-254482-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472365.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1885dupT	p.Tyr629LeufsTer14	frameshift_variant	Exon 14 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1885dupT	p.Tyr629LeufsTer14	frameshift_variant	Exon 14 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*618dupT		non_coding_transcript_exon_variant	Exon 13 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*618dupT		3_prime_UTR_variant	Exon 13 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000596 AC: 1 AN: 167820 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000216

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000210 AC: 3 AN: 1426970 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 2 AN XY: 706630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1GG Pathogenic:1

Jul 31, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 11, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation and affect the functionally important C-terminal region, as the last 36 amino acids are lost and replaced with 13 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Kim 2012, Stenson 2014); Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 21, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1885dupT pathogenic mutation, located in coding exon 14 of the SDHA gene, results from a duplication of T at nucleotide position 1885, causing a translational frameshift with a predicted alternate stop codon (p.Y629Lfs*14). This alteration occurs at the 3' terminus of theSDHA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 36 amino acids of the protein. However, premature stop codons 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). In addition, this alteration has been detected in multiple individuals with a paraganglioma (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Paragangliomas 5 Pathogenic:1

Nov 27, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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

Feb 10, 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 472365). This premature translational stop signal has been observed in individual(s) with paraganglioma and pheochromocytoma (Invitae). This variant is present in population databases (rs750865703, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr629Leufs*14) in the SDHA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the SDHA protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750865703; hg19: chr5-254597;