rs121908051

Variant names:

• chr16-67944001-G-A
• rs121908051
• NM_000229.2:c.101C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-67944001-G-A
• chr16-67944001-G-C
• chr16-67944001-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000229.2(LCAT):​c.101C>T​(p.Pro34Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000716 in 1,395,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 16-67944001-G-A is Pathogenic according to our data. Variant chr16-67944001-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67944001-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCAT	NM_000229.2	c.101C>T	p.Pro34Leu	missense_variant	Exon 1 of 6	ENST00000264005.10	NP_000220.1
SLC12A4	NM_005072.5	c.*839C>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000316341.8	NP_005063.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10	c.101C>T	p.Pro34Leu	missense_variant	Exon 1 of 6	1	NM_000229.2	ENSP00000264005.5
SLC12A4	ENST00000316341	c.*839C>T		3_prime_UTR_variant	Exon 24 of 24	1	NM_005072.5	ENSP00000318557.3
LCAT	ENST00000575467.5	n.101C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000460653.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000716 AC: 10 AN: 1395980 Hom.: 0 Cov.: 32 AF XY: 0.00000436 AC XY: 3 AN XY: 688330

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000650

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 34 of the LCAT protein (p.Pro34Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with fish-eye disease (PMID: 1571050, 24636183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro10Leu. ClinVar contains an entry for this variant (Variation ID: 3662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Norum disease;C0342895:Fish-eye disease Pathogenic:1

Jan 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fish-eye disease Pathogenic:1

Jan 31, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.74
MutPred		0.86		Loss of catalytic residue at P33 (P = 0.0191);
MVP		0.97
MPC		1.2
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.76

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: rs121908051; hg19: chr16-67977904;