rs771593214

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_004168.4(SDHA):c.1813G>A(p.Asp605Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,451,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D605H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.92

Publications

2 publications found

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]

SDHA Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
pheochromocytoma/paraganglioma syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial complex II deficiency, nuclear type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
neurodegeneration with ataxia and late-onset optic atrophy
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
gastrointestinal stromal tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex II deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1GG
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.1813G>A	p.Asp605Asn	missense_variant	Exon 14 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 link	c.1813G>A	p.Asp605Asn	missense_variant	Exon 14 of 15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 link	n.*546G>A		non_coding_transcript_exon_variant	Exon 13 of 24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 link	n.*546G>A		3_prime_UTR_variant	Exon 13 of 24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000842

AC:

AN:

237568

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000693

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1451162

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720710

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33196

American (AMR)

AF:

0.0000922

AC:

AN:

43404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.000101

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

84364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106824

Other (OTH)

AF:

0.00

AC:

AN:

59986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1GG

Uncertain:1

Mar 09, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jul 15, 2024

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 -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Uncertain:1

Feb 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid with asparagine at codon 605 of the SDHA protein (p.Asp605Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SDHA-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1813G>A (p.D605N) alteration is located in exon 14 (coding exon 14) of the SDHA gene. This alteration results from a G to A substitution at nucleotide position 1813, causing the aspartic acid (D) at amino acid position 605 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SDHA-related disorder

Uncertain:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SDHA c.1813G>A variant is predicted to result in the amino acid substitution p.Asp605Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0069% of alleles in individuals of African descent in gnomAD. This variant is interpreted as uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/539636/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;D;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.3

.;N;N;D

REVEL

Uncertain

0.44

Sift

Benign

0.059

.;T;D;D

Sift4G

Uncertain

0.035

D;T;T;D

Polyphen

0.84, 1.0

.;P;D;.

Vest4

0.72

MutPred

0.69

.;Loss of ubiquitination at K608 (P = 0.0288);.;.;

MVP

0.82

MPC

0.55

ClinPred

0.66

GERP RS

4.0

Varity_R

0.30

gMVP

0.85

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over