rs1554411234

Variant names:

• chr7-50463322-C-A
• rs1554411234
• NM_001082971.2:c.1352G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001082971.2(DDC):​c.1352G>T​(p.Cys451Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

Genes affected

DDC (HGNC:2719): (dopa decarboxylase) The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]

DDC Gene-Disease associations (from GenCC):

• aromatic L-amino acid decarboxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001082971.2
• 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 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.40928 (below the threshold of 3.09). Trascript score misZ: 1.0771 (below the threshold of 3.09). GenCC associations: The gene is linked to aromatic L-amino acid decarboxylase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 7-50463322-C-A is Pathogenic according to our data. Variant chr7-50463322-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488382.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDC	NM_001082971.2	c.1352G>T	p.Cys451Phe	missense_variant	Exon 14 of 15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.1352G>T	p.Cys451Phe	missense_variant	Exon 14 of 15	1	NM_001082971.2	ENSP00000403644.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase Pathogenic:1

Oct 17, 2016

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Two heterozygous missense variants were identified in the DDC gene, NM_001082971.1(DDC):c.1352G>T and NM_001082971.1(DDC):c.1073G>A (chr7:50531020C>A and chr7:50537838C>T, respectively). The NM_001082971.1(DDC):c.1352G>T in exon 14 of the DDC gene is predicted to create a change of a cysteine to a phenylalanine at amino acid position 451, NP_001076440.1(DDC):p.(Cys451Phe), which is considered significant. The cysteine at this position has very highly conservation and therefore, Grantham assessment (A-GVGD) is likely pathogenic. In silico software predicts this variant to be disease causing. It is not situated in a known functional domain. This variant has not been previously observed in our cohort and is not present in population databases. It has not been previously reported in other clinical cases however, functional studies on missense variants downstream of this variant showed reduced enzyme activity (Verbeek MM. et al.,2007). Based on current information, and in association with the NM_001082971.1(DDC):c.1073G>A variant, this variant has been classified as LIKELY PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;T;.;.;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;M
PhyloP100		7.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.3	D;.;.;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;.;.;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D
Vest4		0.95
MutPred		0.61		Gain of MoRF binding (P = 0.0818);.;.;.;.;.;Gain of MoRF binding (P = 0.0818);
MVP		0.75
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.93
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554411234; hg19: chr7-50531020;