rs771317809

Variant names:

• chr7-50470140-C-T
• rs771317809
• NM_001082971.2:c.1073G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-50470140-C-T
• chr7-50470140-C-A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001082971.2(DDC):​c.1073G>A​(p.Arg358His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,044 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 (★★). ClinVar reports functional evidence for this variant: "SCV000516849: The R358H substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R358H variant is a conservative change at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (R347Q) has been reported in the Human Gene Mutation Database in association with AADC deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. no" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.30
• Publications: 5 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000516849: The R358H substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R358H variant is a conservative change at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (R347Q) has been reported in the Human Gene Mutation Database in association with AADC deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. no; SCV000680011: Functional studies showed reduced enzyme activity (Verbeek MM. et al.,2007).; SCV002176705: Experimental studies have shown that this missense change affects DDC function (PMID: 29356298).
• 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, 0.976
• PP5: Variant 7-50470140-C-T is Pathogenic according to our data. Variant chr7-50470140-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 379626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082971.2. 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
	DDC	NM_001082971.2	MANE Select	c.1073G>A	p.Arg358His	missense	Exon 12 of 15	NP_001076440.2	A0A0S2Z3N4
	DDC	NM_000790.4		c.1073G>A	p.Arg358His	missense	Exon 12 of 15	NP_000781.2	P20711-1
	DDC	NM_001242886.2		c.959G>A	p.Arg320His	missense	Exon 11 of 14	NP_001229815.2	A0A087WV24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDC	ENST00000444124.7	TSL:1 MANE Select	c.1073G>A	p.Arg358His	missense	Exon 12 of 15	ENSP00000403644.2	P20711-1
	DDC	ENST00000357936.9	TSL:1	c.1073G>A	p.Arg358His	missense	Exon 12 of 15	ENSP00000350616.5	P20711-1
	DDC	ENST00000897740.1		c.1217G>A	p.Arg406His	missense	Exon 13 of 16	ENSP00000567799.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251392 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461044 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726912

African (AFR) AF: 0.00 AC: 0 AN: 33460

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111332

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000495 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Deficiency of aromatic-L-amino-acid decarboxylase (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.95		Loss of MoRF binding (P = 0.0412)
MVP		0.87
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs771317809; hg19: chr7-50537838; COSMIC: COSV105275111;