chr19-11105604-TGGGCGGGGCCA-T

Variant names:

• chr19-11105604-TGGGCGGGGCCA-T
• rs777512182
• NM_000527.5:c.694+8_694+18delCGGGGCCAGGG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The NM_000527.5(LDLR):​c.694+8_694+18delCGGGGCCAGGG variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 1,006,926 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: LDLR NM_000527.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 8.22
• Publications: 1 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 19-11105604-TGGGCGGGGCCA-T is Benign according to our data. Variant chr19-11105604-TGGGCGGGGCCA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 630368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.694+8_694+18delCGGGGCCAGGG		splice_region_variant, intron_variant	Intron 4 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.694+5_694+15delGGGCGGGGCCA		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000780 AC: 19 AN: 243694 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000526 AC: 53 AN: 1006926 Hom.: 1 AF XY: 0.0000788 AC XY: 40 AN XY: 507892

African (AFR) AF: 0.00 AC: 0 AN: 23278

American (AMR) AF: 0.00 AC: 0 AN: 39246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18300

East Asian (EAS) AF: 0.00 AC: 0 AN: 22408

South Asian (SAS) AF: 0.000637 AC: 50 AN: 78456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 745290

Other (OTH) AF: 0.0000751 AC: 3 AN: 39930

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:2

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.694+8_694+18del11 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-05 in 1153438 control chromosomes, predominantly at a frequency of 0.0006 within the South Asian subpopulation in the gnomAD database (v4), including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.694+8_694+18del11 has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Aruljothi_2016) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26927322). ClinVar contains an entry for this variant (Variation ID: 630368). Based on the evidence outlined above, the variant was classified as likely benign. -

Hypercholesterolemia, familial, 1 Benign:1

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 22, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2
Mutation Taster		=14/86	disease causing

Splicing

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

Other links and lift over

dbSNP: rs777512182; hg19: chr19-11216280;