rs1554093461

Positions:

• chr5-173232937-CCA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004387.4(NKX2-5):​c.605_606del​(p.Leu202ArgfsTer49) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.58

Genes affected

NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173232937-CCA-C is Pathogenic according to our data. Variant chr5-173232937-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 536136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173232937-CCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.605_606del	p.Leu202ArgfsTer49	frameshift_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.*558_*559del		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2	c.*404_*405del		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.605_606del	p.Leu202ArgfsTer49	frameshift_variant	2/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.*558_*559del		3_prime_UTR_variant	2/2	1
NKX2-5	ENST00000521848.1	c.*404_*405del		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2017

- -

Atrial septal defect 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 536136). This premature translational stop signal has been observed in individuals with atrial septal defects and atrioventricular conduction abnormalities (PMID: 15689439). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu202Argfs*49) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the NKX2-5 protein. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jul 13, 2016

This variant has been seen in 3 cases (all from same family, does not include this patient's family). The variant has not been previously reported in ClinVar. There is weak case data as only three individuals from one family have been reported in the literature (Sarkozy et al. 2005). This study sequenced the NKX2.5 and GATA4 genes of 16 familial and 13 sporadic cases of pediatric atrial septal defects (ASDs). The c.605_606delTG variant in NKX2.5 was identified in one proband with ASD and AV conduction anomalies, and then identified in his mother and maternal grandmother who were also affected with ASD and AV conduction anomalies. The Leucine at codon 202 is moderately conserved across species, as are neighboring amino acids. Other pathogenic variants have been reported as causing frameshift and/or truncating mutations in this domain (5 in ClinVar). Previous functional studies of mutations in the NKX2-5 homeodomain have demonstrated their reduced transactivation and DNA binding ability (Zhu et al., 2000). In total the variant has not been seen in published controls and individuals from publicly available population datasets. There is no delTG variation at codon 605-606 (chr5: 172659941_172659942) listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 7/2016). This particular region was covered in ~80,000 individuals in the ExAC database. The variant is also absent from 1000 Genomes and NHLBI EVS control population databases, indicating its rarity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554093461; hg19: chr5-172659940;