rs1555013840

Variant names:

• chr11-66849073-T-TATCA
• rs1555013840
• NM_001040716.2:c.3359_3362dupTGAT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001040716.2(PC):​c.3359_3362dupTGAT​(p.Ile1123ArgfsTer50) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PC NM_001040716.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.76
• Publications: 0 publications found

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

PC Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-66849073-T-TATCA is Pathogenic according to our data. Variant chr11-66849073-T-TATCA is described in ClinVar as Pathogenic. ClinVar VariationId is 555085.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	NM_001040716.2	MANE Select	c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 23 of 23	NP_001035806.1	P11498-1
	PC	NM_000920.4		c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 22 of 22	NP_000911.2	P11498-1
	PC	NM_001439352.1		c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 23 of 23	NP_001426281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	ENST00000393960.7	TSL:5 MANE Select	c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 23 of 23	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 21 of 21	ENSP00000377527.2	P11498-1
	PC	ENST00000393958.7	TSL:1	c.3359_3362dupTGAT	p.Ile1123ArgfsTer50	frameshift	Exon 22 of 22	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Pyruvate carboxylase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

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

Other links and lift over

dbSNP: rs1555013840; hg19: chr11-66616544;