VCV002136808.4 - ClinVar

NM_001174147.2(LMX1B):c.175T>C (p.Cys59Arg)

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001174147.2(LMX1B):c.175T>C (p.Cys59Arg)

Variation ID: 2136808 Accession: VCV002136808.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.3 9: 126615418 (GRCh38) [ NCBI UCSC ] 9: 129377697 (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	Feb 8, 2023	Oct 8, 2024	Oct 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001174147.2:c.175T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001167618.1:p.Cys59Arg	missense
NM_001174146.2:c.175T>C	NP_001167617.1:p.Cys59Arg	missense
NM_002316.3:c.175T>C
NM_002316.4:c.175T>C	NP_002307.2:p.Cys59Arg	missense
NC_000009.12:g.126615418T>C
NC_000009.11:g.129377697T>C
NG_017039.1:g.5976T>C
LRG_1014:g.5976T>C
LRG_1014t1:c.175T>C	LRG_1014p1:p.Cys59Arg
LRG_1014t2:c.175T>C	LRG_1014p2:p.Cys59Arg
LRG_1014t3:c.175T>C	LRG_1014p3:p.Cys59Arg

... more HGVS ... less HGVS

Protein change

C59R

Other names

Canonical SPDI

NC_000009.12:126615417:T:C

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.

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

Links

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.
LMX1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	592	633

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 provided	Pathogenic (1)	criteria provided, single submitter	Oct 13, 2022	RCV003062230.3
LMX1B-related disorder	Likely pathogenic (1)	no assertion criteria provided	Oct 20, 2023	RCV003973630.2

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.
Pathogenic (Oct 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441456.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10571942‚ 12215822‚ 34546508 Comment: This variant disrupts the p.Cys59 amino acid residue in LMX1B. Other variant(s) that disrupt this residue have been observed in individuals with LMX1B-related conditions (PMID: … (more) This variant disrupts the p.Cys59 amino acid residue in LMX1B. Other variant(s) that disrupt this residue have been observed in individuals with LMX1B-related conditions (PMID: 10571942, 12215822, 34546508), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 59 of the LMX1B protein (p.Cys59Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nail-patella syndrome (PMID: 10571942; Invitae). This variant is also known as C36R. 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 expected to disrupt LMX1B protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Oct 20, 2023)	no assertion criteria provided Method: clinical testing	LMX1B-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004795807.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The LMX1B c.175T>C variant is predicted to result in the amino acid substitution p.Cys59Arg. This variant was reported in an individual with nail-patella syndrome (Reported … (more) The LMX1B c.175T>C variant is predicted to result in the amino acid substitution p.Cys59Arg. This variant was reported in an individual with nail-patella syndrome (Reported as 106T>C, C36R in Clough et al 1999. PubMed ID: 10571942). A different amino acid change at this position (p.Cys59Ser) has also been reported in an individual with nail-patella syndrome (Reported as 107G>C, C36S in Clough et al 1999. PubMed ID: 10571942). An outside lab has reported this variant as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2136808/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)

Comment:

This variant disrupts the p.Cys59 amino acid residue in LMX1B. Other variant(s) that disrupt this residue have been observed in individuals with LMX1B-related conditions (PMID: 10571942, 12215822, 34546508), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 59 of the LMX1B protein (p.Cys59Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nail-patella syndrome (PMID: 10571942; Invitae). This variant is also known as C36R. 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 expected to disrupt LMX1B protein function. For these reasons, this variant has been classified as Pathogenic.

Comment:

The LMX1B c.175T>C variant is predicted to result in the amino acid substitution p.Cys59Arg. This variant was reported in an individual with nail-patella syndrome (Reported as 106T>C, C36R in Clough et al 1999. PubMed ID: 10571942). A different amino acid change at this position (p.Cys59Ser) has also been reported in an individual with nail-patella syndrome (Reported as 107G>C, C36S in Clough et al 1999. PubMed ID: 10571942). An outside lab has reported this variant as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2136808/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.

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

Title	Author	Journal	Year	Link
Mutational landscape of TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2 and WT1 genes associated with Steroid resistant nephrotic syndrome.	Thakor JM	Molecular biology reports	2021	PMID: 34546508
Nail-patella syndrome. Overview on clinical and molecular findings.	Bongers EM	Pediatric nephrology (Berlin, Germany)	2002	PMID: 12215822
Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients.	Clough MV	Human mutation	1999	PMID: 10571942

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001174147.2(LMX1B):c.175T>C (p.Cys59Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...