VCV000380186.41 - ClinVar

NM_003982.4(SLC7A7):c.272C>T (p.Ala91Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003982.4(SLC7A7):c.272C>T (p.Ala91Val)

Variation ID: 380186 Accession: VCV000380186.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 22813127 (GRCh38) [ NCBI UCSC ] 14: 23282336 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 8, 2017	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003982.4:c.272C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003973.3:p.Ala91Val	missense
NM_001126105.3:c.272C>T	NP_001119577.1:p.Ala91Val	missense
NM_001126106.4:c.272C>T	NP_001119578.1:p.Ala91Val	missense
NC_000014.9:g.22813127G>A
NC_000014.8:g.23282336G>A
NG_012851.2:g.21694C>T
LRG_695:g.21694C>T
LRG_695t2:c.272C>T	LRG_695p2:p.Ala91Val
LRG_695t3:c.272C>T	LRG_695p3:p.Ala91Val

... more HGVS ... less HGVS

Protein change

A91V

Other names

Canonical SPDI

NC_000014.9:22813126:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00419 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00419

1000 Genomes Project 30x 0.00468

Exome Aggregation Consortium (ExAC) 0.01225

Trans-Omics for Precision Medicine (TOPMed) 0.01275

The Genome Aggregation Database (gnomAD) 0.01617

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01430

Links

ClinGen: CA7104737 dbSNP: rs11568438 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC7A7		-	-	GRCh38 GRCh37	756	821

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	May 3, 2021	RCV000424204.3
Lysinuric protein intolerance	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000553552.18
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV001729587.19
Autoinflammatory syndrome	Benign (1)	criteria provided, single submitter	Apr 19, 2022	RCV002263681.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Dec 07, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517952.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lysinuric protein intolerance Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001271344.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (May 03, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001623407.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Comment: Variant summary: SLC7A7 c.272C>T (p.Ala91Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging … (more) Variant summary: SLC7A7 c.272C>T (p.Ala91Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 251372 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC7A7 causing Lysinuric Protein Intolerance phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.272C>T in individuals affected with Lysinuric Protein Intolerance and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lysinuric protein intolerance Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002045752.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022
Benign (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542951.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Lysinuric protein intolerance Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000632018.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005232752.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545157.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: SLC7A7: BS1, BS2 Number of individuals with the variant: 26
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977821.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979034.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (Nov 27, 2019)	no assertion criteria provided Method: clinical testing	Lysinuric protein intolerance Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002091197.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074758.1 First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022	Comment: Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less) Clinical Features: Phenotypic abnormality (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-27 Testing laboratory interpretation: Benign
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant summary: SLC7A7 c.272C>T (p.Ala91Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 251372 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC7A7 causing Lysinuric Protein Intolerance phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.272C>T in individuals affected with Lysinuric Protein Intolerance and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Comment:

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs11568438 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_003982.4(SLC7A7):c.272C>T (p.Ala91Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11568438 ...