NM_000527.5(LDLR):c.1235T>C (p.Met412Thr) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 19, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001377885.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1235T>C (p.Met412Thr)]

NM_000527.5(LDLR):c.1235T>C (p.Met412Thr)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1235T>C (p.Met412Thr)

HGVS:

NC_000019.10:g.11113326T>C
NG_009060.1:g.28946T>C
NM_000527.5:c.1235T>CMANE SELECT
NM_001195798.2:c.1235T>C
NM_001195799.2:c.1112T>C
NM_001195800.2:c.731T>C
NM_001195803.2:c.854T>C
NP_000518.1:p.Met412Thr
NP_000518.1:p.Met412Thr
NP_001182727.1:p.Met412Thr
NP_001182728.1:p.Met371Thr
NP_001182729.1:p.Met244Thr
NP_001182732.1:p.Met285Thr
LRG_274t1:c.1235T>C
LRG_274:g.28946T>C
LRG_274p1:p.Met412Thr
NC_000019.9:g.11224002T>C
NM_000527.4:c.1235T>C
c.1235T>C

Protein change:

M244T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001000; dbSNP: rs879254842

NCBI 1000 Genomes Browser:

rs879254842

Molecular consequence:

NM_000527.5:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1112T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.731T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.854T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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DLAT [Macaca nemestrina]
DLAT [Macaca nemestrina]
Gene ID:105493615

Gene
KLRG2 [Mandrillus leucophaeus]
KLRG2 [Mandrillus leucophaeus]
Gene ID:105550523

Gene
ENSAMXP00000000937 (0)
Protein
ENSPFOP00000018181 (0)
Protein
ENSPTRP00000042219 (0)
Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575333	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 19, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20599862, 11194027, 16406299, 28492532
SCV002086414	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Nov 12, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575333

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 19, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002086414

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Nov 12, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two novel D151Y and M391T LDLR mutations causing LDLR transport defects in Thai patients with familial hypercholesterolemia.

Jeenduang N, Ruangpracha A, Promptmas C, Pongrapeeporn KU, Porntadavity S.

Clin Chim Acta. 2010 Nov 11;411(21-22):1656-61. doi: 10.1016/j.cca.2010.06.021. Epub 2010 Jun 26.

PubMed [citation]

PMID:: 20599862

Mutation analysis of exon 9 of the LDL receptor gene in Thai subjects with primary hypercholesterolemia.

Yamwong P, Pongrapeeporn KU, Thepsuriyanont P, Amornrattana A, Somkasettrin A, Sribhen K.

J Med Assoc Thai. 2000 Nov;83 Suppl 2:S81-8.

PubMed [citation]

PMID:: 11194027

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001575333.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect LDLR protein function (PMID: 20599862). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 11194027, 16406299). It has also been observed to segregate with disease in related individuals. This variant is also known as M391T in the literature. ClinVar contains an entry for this variant (Variation ID: 251745). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 412 of the LDLR protein (p.Met412Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002086414.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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