rs397517237

Positions:

• chr10-74112023-CTGT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_014000.3(VCL):​c.2862_2864del​(p.Leu955del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,614,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: VCL NM_014000.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:9
• Conservation: PhyloP100: 7.46

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014000.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-74112023-CTGT-C is Benign according to our data. Variant chr10-74112023-CTGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=4}. Variant chr10-74112023-CTGT-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0013 (198/152346) while in subpopulation AFR AF= 0.0045 (187/41580). AF 95% confidence interval is 0.00397. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.2862_2864del	p.Leu955del	inframe_deletion	19/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2746-2159_2746-2157del		intron_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2862_2864del	p.Leu955del	inframe_deletion	19/22	1	NM_014000.3	ENSP00000211998
VCL	ENST00000372755.7	c.2746-2159_2746-2157del		intron_variant		1		ENSP00000361841	P1
VCL	ENST00000623461.3	n.5549-2159_5549-2157del		intron_variant, non_coding_transcript_variant		1
VCL	ENST00000624354.3	c.*2617_*2619del		3_prime_UTR_variant, NMD_transcript_variant	18/21	2		ENSP00000485551

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000298 AC: 75 AN: 251466 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135906

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461892 Hom.: 0 AF XY: 0.0000784 AC XY: 57 AN XY: 727248

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74496

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.00150

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	This variant is associated with the following publications: (PMID: 24062880, 11815424, 27532257, 24503780, 23861362, 16236538) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The VCL p.Leu955del variant was identified in 2 of 2440 proband chromosomes (frequency: 0.00082) from individuals or families with arrhythmia, cardiomyopathy, or a family history of sudden death and was not identified in 1000 control chromosomes from healthy individuals (Olson_2002_PMID:11815424; Ng_2013_PMID:23861362). The variant was also identified in dbSNP (ID: rs397517237) and ClinVar (classified as a VUS by three submitters, likely benign by five submitters and benign by Invitae ) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 115 of 282866 chromosomes (1 homozygous) at a frequency of 0.000407 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 112 of 24974 chromosomes (freq: 0.004485), Other in 1 of 7226 chromosomes (freq: 0.000138) and Latino in 2 of 35440 chromosomes (freq: 0.000056), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or South Asian populations. This variant is an in-frame deletion resulting in the removal of a leucine (leu) residue at codon 955; the impact of this alteration on VCL protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 09, 2019	The VCL c.2862_2864del; p.Leu955del variant (rs397517237) is reported in the literature in three individuals who were diagnosed with cardiomyopathy or hyperdynamic left ventricular function (Ng 2013, Olson 2002, and Walsh 2017); however, inheritance and detailed clinical information were not reported for these individuals. This variant deletes a single leucine residue leaving the rest of the protein in-frame. While functional studies demonstrate that the p.Leu955del variant alters actin filament organization, the clinical relevance of these observations is unclear (Olson 2002). The p.Leu955del variant found in the African population with an allele frequency of 0.45% (112/24974 alleles, including a single homozygote) in the Genome Aggregation Database, and is listed in ClinVar with conflicting interpretations of pathogenicity (Variation ID: 45602). Therefore, based on the available information, the clinical significance of the p.Leu955del variant cannot be determined with certainty. References: Ng et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Olson et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002 Jan 29;105(4):431-7. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2022	- -

Dilated cardiomyopathy 1W Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2015	p.Leu955del in exon 19 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (50/10406) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs397517237). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2018	Variant summary: VCL c.2862_2864delGTT (p.Leu955del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0004 in 278208 control chromosomes, predominantly at a frequency of 0.0045 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 180-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.2862_2864delGTT, has been reported in the literature in individuals affected with Cardiomyopathy (Ng_2013, Olson_2002, Walsh_2017, Pugh_DSC2_GIM_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Olson_2002). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x4, VUS x1, benign x1). Based on the evidence outlined above, the variant was classified as likely benign. -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

VCL NM_014000.2 exon 19 p.Leu955del (c.2862_2864del): This variant has been reported in the literature in two individuals with DCM (Olson 2002 PMID:11815424, Walsh 2017 PMID:27532257). However, this variant is also present in 0.4% (112/24974) of African alleles in the Genome Aggregation Database, including one homozygote (http://gnomad.broadinstitute.org/variant/10-75871781-CTGT-C) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:45602). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. An in vitro functional study predicted that this variant may impact the protein (Olson 2002 PMID:11815424). However, this study may not accurately represent in vivo biological function. This variant represents an in-frame deletion of one amino acid at position 955 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Dilated cardiomyopathy with left ventricular noncompaction Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Oct 01, 2015

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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: rs397517237; hg19: chr10-75871781;