rs121434393

Variant names:

• chr11-101453674-T-A
• rs121434393
• NM_004621.6:c.2620A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004621.6(TRPC6):​c.2620A>T​(p.Lys874*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC6 NM_004621.6 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.99
• Publications: 13 publications found

Genes affected

TRPC6 (HGNC:12338): (transient receptor potential cation channel subfamily C member 6) The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Activation of this channel occurs independently of protein kinase C and is not triggered by low levels of intracellular calcium. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2). [provided by RefSeq, Mar 2009]

TRPC6 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-101453674-T-A is Pathogenic according to our data. Variant chr11-101453674-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6154.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004621.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	NM_004621.6	MANE Select	c.2620A>T	p.Lys874*	stop_gained	Exon 12 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.2272A>T	p.Lys758*	stop_gained	Exon 10 of 11	NP_001426264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.2620A>T	p.Lys874*	stop_gained	Exon 12 of 13	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.2455A>T	p.Lys819*	stop_gained	Exon 11 of 12	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.2272A>T	p.Lys758*	stop_gained	Exon 10 of 11	ENSP00000343672.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys874*) in the TRPC6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the TRPC6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial focal segmental glomerulosclerosis (PMID: 15924139). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6154). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect TRPC6 function (PMID: 15924139, 19129465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Mar 15, 2024

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the TRPC6 gene demonstrated a sequence change, c.2620A>T, which results in the creation of a premature stop codon at amino acid position 874, p.Lys874*. This sequence change is located in the penultimate exon of the gene, therefore the mutant mRNA may escape nonsense mediated decay; however, functional studies are needed to prove this conclusively. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs121434393). This sequence change has previously been described in a family with autosomal dominant focal segmental glomerulosclerosis (FSGS); it was also present in some of the reportedly asymptomatic family members (PMID: 15924139). This sequence change did not show altered current amplitude (not significantly different from wild type) when expressed in HEK cells (PMID: 15924139). Another experimental assay showed that this variant did not show significant difference in basal NFAT-responsive reporter activity when compared to wild type (PMID: 19129465). Due to these collective evidences and the fact that loss of function is not an established mechanism of disease for this gene; the clinical significance of the p.Lys874* change remains unknown at this time.

Focal segmental glomerulosclerosis 2 Pathogenic:1

Jul 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.0
Vest4		0.92
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434393; hg19: chr11-101324405;