rs137853208

Variant names:

• chr7-50504025-G-A
• rs137853208
• NM_001082971.2:c.749C>T

Variant summary

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

The NM_001082971.2(DDC):​c.749C>T​(p.Ser250Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.60
• Publications: 12 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: 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 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, 0.873
• PP5: Variant 7-50504025-G-A is Pathogenic according to our data. Variant chr7-50504025-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17810.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
DDC	NM_001082971.2	c.749C>T	p.Ser250Phe	missense_variant	Exon 7 of 15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.749C>T	p.Ser250Phe	missense_variant	Exon 7 of 15	1	NM_001082971.2	ENSP00000403644.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

⚠️ 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: 33474

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: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase Pathogenic:3

May 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DDC c.749C>T (p.Ser250Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes in GnomAD. Homozygous c.749C>T has been reported in the literature in multiple individuals affected with Deficiency of Aromatic-L-Amino-Acid Decarboxylase (example: Pons_2004, Veerbeek_2007). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example: Montioli_ 2003_2014, Caine_2017). The most pronounced variant effect results in a 7-fold reduction of catalytic efficiency of normal activity, and p.Ser250Phe knock-in mice reassemble a mild aromatic L-amino acid decarboxylase (AADC) deficiency. The following publications have been ascertained in the context of this evaluation (PMID: 29851841, 15079002, 23321058, 17240182, 24865461, 28973165). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 15079002, 17533144, 20505134, 29851841). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DDC function (PMID: 23321058, 24865461, 28973165). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 17810). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 250 of the DDC protein (p.Ser250Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T;.;.;.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;M;M
PhyloP100		7.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D;.;.;.;D;D;D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.;.;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.
Vest4		0.81
MutPred		0.64		Loss of relative solvent accessibility (P = 0.1807);.;.;.;.;.;Loss of relative solvent accessibility (P = 0.1807);Loss of relative solvent accessibility (P = 0.1807);
MVP		0.84
MPC		1.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs137853208; hg19: chr7-50571723;