rs199751308

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_054012.4(ASS1):c.929A>G(p.Lys310Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,984 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K310Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.72

Publications

5 publications found

Variant links:

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]

ASS1 Gene-Disease associations (from GenCC):

citrullinemia type I
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
acute neonatal citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
adult-onset citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ASS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_054012.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-130489422-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6339.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

PP5

Variant 9-130489423-A-G is Pathogenic according to our data. Variant chr9-130489423-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 365260.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
ASS1	NM_054012.4 link	c.929A>G	p.Lys310Arg	missense_variant	Exon 12 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4 link	c.929A>G	p.Lys310Arg	missense_variant	Exon 13 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 link	c.929A>G	p.Lys310Arg	missense_variant	Exon 12 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251470

AF XY:

0.0000294

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:3

Jun 09, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Citrullinemia

Pathogenic:2

Jun 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys310 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been observed in individuals with ASS1-related conditions (PMID: 15266621), which suggests that this may be a clinically significant amino acid residue. 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) performed at Invitae indicates that this missense variant is not expected to disrupt ASS1 protein function. ClinVar contains an entry for this variant (Variation ID: 365260). This missense change has been observed in individual(s) with clinical features of ASS1-related conditions (PMID: 12815590, 15863597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199751308, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 310 of the ASS1 protein (p.Lys310Arg). -

Jun 05, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ASS1 c.929A>G (p.Lys310Arg) results in a conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 2.8e-05 in 251470 control chromosomes. c.929A>G has been observed in individual(s) affected with Citrullinemia Type I (Gao_2003, Enns_2005, internal testing). These data indicate that the variant is likely to be associated with disease. A different variant affecting this residue (c.928A>C p.K310Q) have been reported in an individual affected with Citrullinemia (Gao_2003), suggesting this residue may be critical for normal protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28111830, 12815590, 15863597). ClinVar contains an entry for this variant (Variation ID: 365260). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Pathogenic:1

Mar 21, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Aug 31, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The K310R variant in the ASS1 gene has been reported in a patient with adult/late-onset classic citrullinemia who had no detectable arginosuccinate synthetase activity in fibroblasts and who also harbored a pathogenic frameshift variant in the ASS1 gene (Gao et al. 2003). The K310R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, K310 is located within the catalytic domain of the argininosuccinate synthetase enzyme and is believed to be involved with dimer interaction, and another missense variant at the same position (K310Q) has been identified in a patient with no detectable argininosuccinate synthetase activity who also harbored a splice site variant in the ASS1 gene (Gao et al. 2003). In summary, we interpret K310R to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

8.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.93

N;N;N

REVEL

Pathogenic

0.82

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.95

MVP

0.97

MPC

0.82

ClinPred

0.56

GERP RS

4.5

Varity_R

0.58

gMVP

0.90

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over