rs1057517754

Variant names:

• chr7-92221936-CTTCTT-C
• rs1057517754
• NM_194454.3:c.1524_1528delAAGAA

Variant summary

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

The NM_194454.3(KRIT1):​c.1524_1528delAAGAA​(p.Arg510CysfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.37

Genes affected

KRIT1 (HGNC:1573): (KRIT1 ankyrin repeat containing) This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

ENSG00000289027 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92221936-CTTCTT-C is Pathogenic according to our data. Variant chr7-92221936-CTTCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92221936-CTTCTT-C is described in Lovd as [Pathogenic]. Variant chr7-92221936-CTTCTT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.1524_1528delAAGAA	p.Arg510CysfsTer8	frameshift_variant	Exon 14 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1524_1528delAAGAA	p.Arg510CysfsTer8	frameshift_variant	Exon 14 of 19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.1524_1528delAAGAA	p.Arg510CysfsTer8	frameshift_variant	Exon 14 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1524_1528delAAGAA	p.Arg510CysfsTer8	frameshift_variant	Exon 13 of 20	4		ENSP00000396352.2

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/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 31, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1524_1528delAAGAA pathogenic variant in the KRIT1 gene causes a frameshift starting with codon Arginine 510, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg510CysfsX8. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this variant has not been previously reported to our knowledge, we interpret it as pathogenic. -

Cerebral cavernous malformation Pathogenic:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cavernous malformations of CNS and retina, cerebral cavernous malformations-1 (CCM) and hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations (MIM#116860). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. This has been reported for variants resulting in familial CCM (PMID: 16571644, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial variability have been reported for variants causing CCM (PMID: 29593473). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three unrelated individuals by clinical laboratories in ClinVar and in another family with cerebral cavernous malformations in the literature (PMID: 30161288). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been observed in three affected siblings and their affected mother (PMID: 30161288). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517754; hg19: chr7-91851250;