chr9-130480419-G-C

Position:

• chr9-130480419-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_054012.4(ASS1):​c.808G>C​(p.Glu270Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,828 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 9.26

Genes affected

ASS1 (HGNC:758): (argininosuccinate synthase 1) The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ASSY_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 9-130480419-G-C is Pathogenic according to our data. Variant chr9-130480419-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557173.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}. Variant chr9-130480419-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.808G>C	p.Glu270Gln	missense_variant	11/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.808G>C	p.Glu270Gln	missense_variant	12/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.808G>C	p.Glu270Gln	missense_variant	11/15	1	NM_054012.4	ENSP00000253004	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251312 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2024	Variant summary: ASS1 c.808G>C (p.Glu270Gln) results in a conservative amino acid change located in the Arginosuccinate synthase C-terminal domain (IPR048268) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251312 control chromosomes. c.808G>C has been reported in the literature in compound heterozygous individuals affected with Citrullinemia Type I (e.g. Vilaseca_2001, Zielonka_2019, Kleijer_2006). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in null enzyme activity in vitro (e.g. Diez-Fernandez_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27287393, 16475226, 11708871, 31469252). ClinVar contains an entry for this variant (Variation ID: 557173). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 22, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 270 of the ASS1 protein (p.Glu270Gln). This variant is present in population databases (rs775163147, gnomAD 0.003%). This missense change has been observed in individual(s) with citrullinemia (PMID: 11708871, 12815590). ClinVar contains an entry for this variant (Variation ID: 557173). 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 C0"). Experimental studies have shown that this missense change affects ASS1 function (PMID: 27287393, 31469252). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Citrullinemia type I Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 12, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Genetique Humaine, Institut de Pathologie et de Genetique	Dec 21, 2023	The c.808G>C p.(Glu270Gln) impacts a highly conserved nucleotide (phyloP: 9.09) and a highly conserved amino acid (down to the yeast). It has 5 occurrences in gnomAD v4. Prediction tools pedict a deleterious effect (19/21), CADD : 28.8, REVEL 0.973. In vitro data revealed complete loss of enzyme activity (0%) (PMID: 27287393). It was reported once in a child who died in the context of hyperammonemia (600µM) after 1 week of life. In this reported child, the second reported variant was p.(Val69Ala) and the ASS1 enzyme activity was abolished in fibroblasts and in liver tissue (PMID: 11708871). The familial segregation confirming the bi-allelic occurence was not reported in the manuscript. Our patient (mild form of ASSD) carries the c.808G>C variant in cis with c.206T>C, inherited from his father, and in trans with c.970G>A, inherited from his mother. Intriguingly, the paternal allele of our patient is composed of the two variants reported in PMID: 11708871, which are presumably in trans in the published patient (severe case). There is second published patient who also carries the same two variants with no reported segregation (PMID: 12815590). In gnomAD, c.206T>C and c.808G>C have the same number of occurrences (v2.1.1 : 2-2, v4.0.0 : 5-5). These two variant might be on the same haplotype and we postulate that there is a third variant in trans that was not found in the first published case (PMID: 11708871). This would explain why our patient has a mild phenotype resulting from an hypomorphic allele c.970G>A (PMID: 14680976) + a severe allele [c.206T>C;c.808G>C]. -

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 19, 2024

Variant summary: G6PC c.808G>C (p.Gly270Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251358 control chromosomes (gnomAD). c.808G>C (also described as c.887G>C by old nomenclature in the literature) has been reported in the literature in at least an individual affected with Glycogen Storage Disease Type Ia (Trioche_2000). In in vitro functional studies, the variant resulted in reduced phosphohydrolase activity compared to wild-type (Shieh_2002). Another variant affecting the same codon (p.Gly270Val) has been reported as pathogenic in ClinVar, suggesting this residue may be clinically important. 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 likely pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 04, 2021

ACMG categories: PM1,PM2,PM3,PP3,PP4 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31469252, 28111830, 11708871, 35281663) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.3	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.98		Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);
MVP		0.97
MPC		0.92
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.98

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: rs775163147; hg19: chr9-133355806;