NM_014270.5(SLC7A9):c.997C>T (p.Arg333Trp) AND Cystinuria

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006143.13

Allele description [Variation Report for NM_014270.5(SLC7A9):c.997C>T (p.Arg333Trp)]

NM_014270.5(SLC7A9):c.997C>T (p.Arg333Trp)

Gene:

SLC7A9:solute carrier family 7 member 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.11

Genomic location:

Preferred name:

NM_014270.5(SLC7A9):c.997C>T (p.Arg333Trp)

HGVS:

NC_000019.10:g.32843932G>A
NG_008258.1:g.30846C>T
NM_001126335.2:c.997C>T
NM_001243036.2:c.997C>T
NM_014270.5:c.997C>TMANE SELECT
NP_001119807.1:p.Arg333Trp
NP_001229965.1:p.Arg333Trp
NP_055085.1:p.Arg333Trp
NC_000019.9:g.33334838G>A
NM_014270.4:c.997C>T
P82251:p.Arg333Trp

Protein change:

R333W; ARG333TRP

Links:

UniProtKB: P82251#VAR_019011; OMIM: 604144.0008; dbSNP: rs121908484

NCBI 1000 Genomes Browser:

rs121908484

Molecular consequence:

NM_001126335.2:c.997C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243036.2:c.997C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014270.5:c.997C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystinuria (CSNU)
Synonyms:: CYSTINURIA, TYPE I; CYSTINURIA, TYPE II; CYSTINURIA, TYPE III; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009067; MedGen: C0010691; Orphanet: 214; OMIM: 220100; Human Phenotype Ontology: HP:0003131

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026325	OMIM	no assertion criteria provided	Pathogenic (Feb 15, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001425264	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2020)	inherited	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV002020730	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002792687	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 30, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004047896	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005202236	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.

Domingo-Gallego A, Pybus M, Bullich G, Furlano M, Ejarque-Vila L, Lorente-Grandoso L, Ruiz P, Fraga G, López González M, Piñero-Fernández JA, Rodríguez-Peña L, Llano-Rivas I, Sáez R, Bujons-Tur A, Ariceta G, Guirado L, Torra R, Ars E.

Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. doi: 10.1093/ndt/gfab019.

PubMed [citation]

PMID:: 33532864

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000026325.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In patients with cystinuria defined as non-type I (see 220100), Font et al. (2001) identified a C-to-T transition at nucleotide 1182, resulting in an arg333-to-trp substitution. The mutation was found in 8% of mutant alleles, third in frequency behind gly105 to arg (604144.0002) and val170 to met (604144.0001).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425264.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020730.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002792687.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The SLC7A9 c.997C>T (p.Arg333Trp) variant has been observed in several individuals affected with cystinuria (Halbritter J et al, Chatzikyriakidou A et al). Experimental studies have shown that this missense change abolishes SLC7A9 cysteine transport (Font MA et al). This variant is reported with the allele frequency (0.0085%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Likely Pathogenic. The amino acid Arg at position 333 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg333Trp in SLC7A9 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005202236.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: SLC7A9 c.997C>T (p.Arg333Trp) 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 8.8e-05 in 251352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC7A9 causing Cystinuria, allowing no conclusion about variant significance. c.997C>T has been reported in the literature in multiple individuals affected with Cystinuria (example, Font_2001). 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 activity in Hela cells (Font_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11157794). ClinVar contains an entry for this variant (Variation ID: 5787). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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