rs1017441235

Positions:

• chr5-254498-A-G
• chr5-254498-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004168.4(SDHA):​c.1900A>G​(p.Thr634Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32737064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1900A>G	p.Thr634Ala	missense_variant	14/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1900A>G	p.Thr634Ala	missense_variant	14/15	1	NM_004168.4	ENSP00000264932	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2018

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SDHA-related disease. ClinVar contains an entry for this variant (Variation ID: 412383). This sequence change replaces threonine with alanine at codon 634 of the SDHA protein (p.Thr634Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2021

The p.T634A variant (also known as c.1900A>G), located in coding exon 14 of the SDHA gene, results from an A to G substitution at nucleotide position 1900. The threonine at codon 634 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.55
DEOGEN2	Benign	0.36	T;D;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.9	.;M;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	.;D;N;D
REVEL	Uncertain	0.50
Sift	Benign	0.45	.;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0, 0.27	.;B;B;.
Vest4		0.25
MutPred		0.29		.;Loss of phosphorylation at T634 (P = 0.0428);.;.;
MVP		0.79
MPC		0.47
ClinPred		0.51	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.67

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: rs1017441235; hg19: chr5-254613;