rs201951824

Positions:

chr7-50476625-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001082971.2(DDC):c.1040G>A(p.Arg347Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000391 in 1,612,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

DDC
NM_001082971.2 missense, splice_region

Scores

Splicing: ADA: 0.9488

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.65

Variant links:

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 links:

DDC (HGNC:):

DDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

PP5

Variant 7-50476625-C-T is Pathogenic according to our data. Variant chr7-50476625-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDC	NM_001082971.2 linkuse as main transcript	c.1040G>A	p.Arg347Gln	missense_variant, splice_region_variant	11/15	ENST00000444124.7	NP_001076440.2	P20711-1Q53Y41A0A0S2Z3N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7 linkuse as main transcript	c.1040G>A	p.Arg347Gln	missense_variant, splice_region_variant	11/15	1	NM_001082971.2	ENSP00000403644.2		P20711-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249548

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1460178

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1040G>A;p.(Arg347Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 202181; PMID: 26994895; 24865461; 30144970; 30952622) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24865461) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Pyridoxal_deC) - PM1. The variant is present at low allele frequencies population databases (rs201951824– gnomAD 0.0002629%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (PMID: 26994895) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 30144970) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Aug 28, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2021	Variant summary: DDC c.1040G>A (p.Arg347Gln) results in a conservative amino acid change located in the Pyridoxal phosphate-dependent transferase, major domain (IPR015421) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249548 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DDC causing Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1040G>A has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (example Veerbeek_2007, Kuster_2018, Dai_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal decarboxylase activity towards L-Dopa substrate as observed by decreased steady state enzyme kinetic parameters (example, Montoli_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 347 of the DDC protein (p.Arg347Gln). This variant is present in population databases (rs201951824, gnomAD 0.01%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 17240182, 23430870, 30144970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 202181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2022	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 31, 2021

ACMG classification criteria: PS3, PS4, PM2, PM3 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2023

Also observed with a second DDC variant in patients with AADC deficiency in published literature (Verbeek et al., 2007; Barth et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate severely reduced catalytic activity (Montioli et al., 2014; Montioli et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32369189, 17240182, 23430870, 20832343, 24865461, 26994895, 29356298, 30144970, 28100251, 31104889, 31975548, 27147232, 33763332, 32111562, 34426522, 34582790, 33083013) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;T;.;.;.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D;D;.;D;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

4.0

H;.;.;.;.;.;H

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.3

D;.;.;.;D;D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0070

D;.;.;.;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

0.97

D;.;.;.;.;.;D

Vest4

0.80

MVP

0.75

MPC

0.33

ClinPred

0.52

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over