NM_177924.5(ASAH1):c.677G>C (p.Arg226Pro) AND Farber lipogranulomatosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 19, 2019
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:: RCV001003317.2

Allele description [Variation Report for NM_177924.5(ASAH1):c.677G>C (p.Arg226Pro)]

NM_177924.5(ASAH1):c.677G>C (p.Arg226Pro)

Gene:

ASAH1:N-acylsphingosine amidohydrolase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p22

Genomic location:

Preferred name:

NM_177924.5(ASAH1):c.677G>C (p.Arg226Pro)

HGVS:

NC_000008.11:g.18061712C>G
NG_008985.2:g.28287G>C
NM_001127505.3:c.659G>C
NM_001363743.2:c.482G>C
NM_004315.6:c.725G>C
NM_177924.5:c.677G>CMANE SELECT
NP_001120977.1:p.Arg220Pro
NP_001350672.1:p.Arg161Pro
NP_004306.3:p.Arg242Pro
NP_808592.2:p.Arg226Pro
NC_000008.10:g.17919221C>G
NG_008985.1:g.28287G>C

Protein change:

R161P

Links:

dbSNP: rs377749094

NCBI 1000 Genomes Browser:

rs377749094

Molecular consequence:

NM_001127505.3:c.659G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363743.2:c.482G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004315.6:c.725G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_177924.5:c.677G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Farber lipogranulomatosis (FRBRL)
Synonyms:: Farber's disease; Farber disease; AC DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009218; MedGen: C0268255; Orphanet: 333; OMIM: 228000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001161401	Medical Affairs, Dicerna Pharmaceuticals	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 19, 2019)	maternal	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001161401

Medical Affairs, Dicerna Pharmaceuticals

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 19, 2019)

maternal

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	2	1	not provided	not provided	yes	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Medical Affairs, Dicerna Pharmaceuticals, SCV001161401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	literature only	PubMed (1)
2	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

"HANSA predicts the variant, c.677G>C, induces the loss of H-bonds and destabilizes the structure near catalytic triad."

DOI [ID: 10.1111/cge.12316]

Description

Variant c.677G>C has been classified as likely pathogenic using the following rationale. Two siblings described in Bashyam et al., 2014, doi: 10.1111/cge.12316 were diagnosed with Farber disease characteristic of Type 1 Farber disease discussed in Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Compound heterozygous variants in the ASAH1 gene, c.677G>C and c.1084C>A, were identified and biparental segregation was noted. Structural analysis using HANSA software predicted variant pathogenicity due to loss of an H-bond resulting in destabilization of catalytic triad structure.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		2	not provided	1	not provided
2	maternal	yes	not provided	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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