chr2-206127898-T-C

Variant names:

• chr2-206127898-T-C
• rs387907199
• NM_005006.7:c.1783A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005006.7(NDUFS1):​c.1783A>G​(p.Thr595Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T595T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFS1 NM_005006.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.97
• Publications: 7 publications found

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NDUFS1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.075123 (below the threshold of 3.09). Trascript score misZ: 0.57926 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, mitochondrial disease, mitochondrial complex I deficiency, nuclear type 5, mitochondrial complex I deficiency, Leigh syndrome with leukodystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 2-206127898-T-C is Pathogenic according to our data. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206127898-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 31914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS1	NM_005006.7	c.1783A>G	p.Thr595Ala	missense_variant	Exon 16 of 19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11	c.1783A>G	p.Thr595Ala	missense_variant	Exon 16 of 19	1	NM_005006.7	ENSP00000233190.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000348 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 595 of the NDUFS1 protein (p.Thr595Ala). This variant is present in population databases (rs387907199, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 21203893, 22310368). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31914). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDUFS1 protein function. Studies have shown that this missense change alters NDUFS1 gene expression (PMID: 21203893). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 06, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22272371, 22142868, 30055843, 21203893, 22310368, 36042640) -

Mitochondrial complex I deficiency, nuclear type 5 Pathogenic:1

Feb 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;T;.;D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.;H;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0050	D;D;D;D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;D;.
Vest4		0.99
MutPred		0.65		Loss of glycosylation at T595 (P = 0.0225);.;.;.;.;Loss of glycosylation at T595 (P = 0.0225);.;
MVP		0.99
MPC		0.29
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs387907199; hg19: chr2-206992622;