16-67944000-C-CG

Position:

• chr16-67944000-C-CG

Variant summary

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

The NM_000229.2(LCAT):​c.101_102insC​(p.His35AlafsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000452 in 1,547,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: LCAT NM_000229.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.40

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

SLC12A4 (HGNC:10913): (solute carrier family 12 member 4) This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

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 16-67944000-C-CG is Pathogenic according to our data. Variant chr16-67944000-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 3661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCAT	NM_000229.2	c.101_102insC	p.His35AlafsTer7	frameshift_variant	1/6	ENST00000264005.10
SLC12A4	NM_005072.5	c.*839_*840insC		3_prime_UTR_variant	24/24	ENST00000316341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCAT	ENST00000264005.10	c.101_102insC	p.His35AlafsTer7	frameshift_variant	1/6	1	NM_000229.2	P1
SLC12A4	ENST00000316341.8	c.*839_*840insC		3_prime_UTR_variant	24/24	1	NM_005072.5	P1
LCAT	ENST00000575467.5	c.101_102insC	p.His35AlafsTer7	frameshift_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151958 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1395878 Hom.: 0 Cov.: 32 AF XY: 0.00000291 AC XY: 2 AN XY: 688292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151958 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74196

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LCAT deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 31, 1991

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2023

This sequence change creates a premature translational stop signal (p.His35Alafs*7) in the LCAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LCAT are known to be pathogenic (PMID: 15994445). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3661). This premature translational stop signal has been observed in individual(s) with clinical features of lecithin-cholesterol acyltransferase (LCAT) deficiency (PMID: 30333156). This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2021

The c.101dupC pathogenic mutation, located in coding exon 1 of the LCAT gene, results from a duplication of C at nucleotide position 101, causing a translational frameshift with a predicted alternate stop codon (p.H35Afs*7). The predicted stop codon occurs within the first 150 nucleotides of the LCAT gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, a significant portion of the protein is affected, and the impacted region is critical for protein function (Schindler PA et al. Protein Sci, 1995 Apr;4:791-803; Peelman F et al. Protein Sci, 1998 Mar;7:587-99; Piper DE et al. J Lipid Res, 2015 Sep;56:1711-9; Glukhova A et al. Nat Commun, 2015 Mar;6:6250). This variant (also referred to as an insertion of C in a string of 6 at position 932-937) has been detected in the homozygous state in an individual with LCAT deficiency, corneal opacities, anemia, and renal disease, and in the heterozygous state in an individual with low HDL cholesterol (Bujo H et al. Biochem Biophys Res Commun, 1991 Dec;181:933-40; Geller AS et al. J Lipid Res, 2018 12;59:2421-2435). Combined, the functional and structural evidence from these studies have shown patients homozygous for this and other mutations predicted to truncate the protein within the first coding exon, demonstrate absent or nearly absent LCAT plasma protein and little to no LCAT enzyme activity in the blood, a result consistent with the removal of many of the sites expected to be most involved in the enzyme's catalytic activity. Furthermore, heterozygous carriers of LCAT mutations have been shown to have variably penetrant expression in a gene-dosage effect pattern, most frequently seen as lower than normal HDL cholesterol, which could contribute to an increased risk for coronary heart disease (Calabresi L et al. Arterioscler Thromb Vasc Biol, 2005 Sep;25:1972-8; Calabresi L et al. Atherosclerosis, 2012 Jun;222:299-306). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs967875404; hg19: chr16-67977903;