7-50537928-C-G

Position:

• chr7-50537928-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PP3_Moderate PP5

The NM_001082971.2(DDC):​c.367G>C​(p.Gly123Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.09

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-AS1 (HGNC:40171): (DDC antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_001082971.2 (DDC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a region_of_interest 2 X approximate tandem repeats (size 120) in uniprot entity DDC_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001082971.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 7-50537928-C-G is Pathogenic according to our data. Variant chr7-50537928-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3003021.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDC	NM_001082971.2	c.367G>C	p.Gly123Arg	missense_variant	4/15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.367G>C	p.Gly123Arg	missense_variant	4/15	1	NM_001082971.2	ENSP00000403644.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000600 AC: 15 AN: 249826 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135260

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000329

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000958 AC: 14 AN: 1461284 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000288 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DDC protein function. This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 20505134, 32369189). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 123 of the DDC protein (p.Gly123Arg). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 27, 2024

Variant summary: DDC c.367G>C (p.Gly123Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249826 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DDC causing Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (6e-05 vs 0.0011), allowing no conclusion about variant significance. c.367G>C has been reported in the literature in the compound heterozygous state in at least one individual affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (Brun_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 20505134). ClinVar contains an entry for this variant (Variation ID: 3003021). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;T;.;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	.;D;D;D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	2.0	M;M;.;.;M;M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;.;.;T;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;T
Polyphen		1.0	D;.;.;.;.;D;.
Vest4		0.91
MutPred		0.81		Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);.;Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);
MVP		0.76
MPC		1.1
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs768596169; hg19: chr7-50605626; COSMIC: COSV63565669;