rs770506764

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004168.4(SDHA):​c.1429C>T​(p.Pro477Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.58
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHANM_004168.4 linkc.1429C>T p.Pro477Ser missense_variant Exon 10 of 15 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHAENST00000264932.11 linkc.1429C>T p.Pro477Ser missense_variant Exon 10 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.*162C>T non_coding_transcript_exon_variant Exon 9 of 24 ENSP00000499215.1 A0A494C1T6
ENSG00000286001ENST00000651543.1 linkn.*162C>T 3_prime_UTR_variant Exon 9 of 24 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251156
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135734
show subpopulations
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461492
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727074
show subpopulations
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:
0.0000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Feb 13, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Aug 31, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Dec 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 477 of the SDHA protein (p.Pro477Ser). This variant is present in population databases (rs770506764, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 412339). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Dilated cardiomyopathy 1GG Uncertain:1
Mar 08, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 24, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P477S variant (also known as c.1429C>T), located in coding exon 10 of the SDHA gene, results from a C to T substitution at nucleotide position 1429. The proline at codon 477 is replaced by serine, 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
T;T;.;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.61
D;D;D;D
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.7
.;L;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.2
.;D;D;D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0070
.;D;D;D
Sift4G
Benign
0.078
T;T;T;T
Polyphen
0.053, 0.29
.;B;B;.
Vest4
0.65
MVP
0.79
MPC
0.51
ClinPred
0.73
D
GERP RS
5.0
Varity_R
0.56
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770506764; hg19: chr5-236711; API